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Abstract:

The invention relates to pyrazoline substituted compounds and methods for
activating PKM2. The compounds and methods are useful in treating or
preventing a disease or disorder selected from cancer, cell proliferative
disorder, inflammatory disorder, metabolic disorder, and immune system
disorder.

Claims:

1. A compound according to Formula I: ##STR00450## or a
pharmaceutically acceptable salt thereof, wherein: W is NRa or is
absent, wherein Ra is (i) a group selected from the group consisting
of a hydrogen, a linear or branched, saturated or unsaturated
C1-C6 alkyl, C(O)Rc, and a linear or branched, saturated
or unsaturated C1-C6 alkoxy; or (ii) Ra and R4a
together with the atoms to which they are attached, form a five to seven
membered heterocycloalkyl or heteroaromatic ring; R1 is selected
from the group consisting of a hydrogen a linear or branched, saturated
or unsaturated C1-C6 alkyl or heteroalkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl, wherein said alkyl, heteroalkyl, cycloalkyl,
heterocycloalkyl, aryl or heteroaryl is unsubstituted or substituted with
one or more Rb, wherein Rb is independently at each occurrence
selected from the group consisting of: u) a linear or branched, saturated
or unsaturated C1-C6 alkyl, v) a linear or branched, saturated
or unsaturated C1-C6 haloalkyl, w) a linear or branched,
saturated or unsaturated C1-C6 alkoxy or aryloxy, x) a linear
or branched, saturated or unsaturated C1-C6 haloalkoxy, y) a
linear or branched, saturated or unsaturated C1-C6
alkylsulfonyl, z) a linear or branched, saturated or unsaturated
C1-C6 thioalkyl or thioaryl, aa) a saturated or unsaturated
C3-C8 cycloalkyl, bb) an aryl, cc) a heteroaryl, dd) a
heterocycloalkyl, ee) hydroxyl, ff) cyano, gg) amino, hh) nitro, ii)
halogen, jj) CORc, kk) COORc, ll) CONRcRd, m)
NHCORc, and nn) NRcRd wherein Rc and Rd are,
each independently, hydrogen or a group selected from a linear or
branched, saturated or unsaturated C1-C6 alkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl; or wherein two Rb on adjacent carbon atoms form a
heteroaryl ring or heterocycloalkyl ring; R2 and R5 are, each
independently, selected from hydrogen, a linear or branched, saturated or
unsaturated C1-C6 alkyl or heteroalkyl, heteroaryl, or aryl,
wherein said alkyl, heteroalkyl, heteroaryl, or aryl is unsubstituted or
substituted with one or more Re, wherein Re is independently at
each occurrence selected from the group consisting of CORf,
COORf, CONRfRg, NHCORf, and NRfRg, wherein
Rf and Rg are, each independently, hydrogen or a group selected
from a linear or branched, saturated or unsaturated C1-C6
alkyl, a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl; R3a, R3b, R3c,
R3d and R3e are, each independently, selected from: v) hydrogen
w) a linear or branched, saturated or unsaturated C1-C6 alkyl,
x) a linear or branched, saturated or unsaturated C1-C6
haloalkyl, y) a linear or branched, saturated or unsaturated
C1-C6 alkoxy or aryloxy, z) a linear or branched, saturated or
unsaturated C1-C6 haloalkoxy, aa) a linear or branched,
saturated or unsaturated C1-C6 alkylsulfonyl, bb) a linear or
branched, saturated or unsaturated C1-C6 thioalkyl or thioaryl,
cc) a saturated or unsaturated C3-C8 cycloalkyl, dd) an aryl,
ee) a heteroaryl, ff) a heterocycloalkyl, gg) hydroxyl, hh) cyano, ii)
amino, jj) nitro, kk) halogen, ll) CORh, m) COORh, m)
CONRhRi, oo) NHCORh, or pp) NRhRi wherein
Rh and Ri are, each independently, hydrogen or a group selected
from a linear or branched, saturated or unsaturated C1-C6
alkyl, a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl; or two adjacent of R3a,
R3b, R3c, R3d and R3e, together with the atoms to
which they are attached, form a C5-C7 cycloalkyl,
heterocycloalkyl, aromatic or heteroaromatic ring; R4b, R4c and
R4d, and a when R4a does not form a five to seven membered ring
with Ra, R4a, are, each independently, selected from: v)
hydrogen w) a linear or branched, saturated or unsaturated
C1-C6 alkyl, x) a linear or branched, saturated or unsaturated
C1-C6 haloalkyl, y) a linear or branched, saturated or
unsaturated C1-C6 alkoxy or aryloxy, z) a linear or branched,
saturated or unsaturated C1-C6 haloalkoxy, aa) a linear or
branched, saturated or unsaturated C1-C6 alkylsulfonyl, bb) a
linear or branched, saturated or unsaturated C1-C6 thioalkyl or
thioaryl, cc) a saturated or unsaturated C3-C8 cycloalkyl, dd)
an aryl, ee) a heteroaryl, ff) a heterocycloalkyl, gg) hydroxyl, hh)
cyano, ii) amino, jj) nitro, kk) halogen, ll) CORj, m) COORj,
m) CONRjRk, oo) NHCORj, or pp) NRjRk wherein
Rj and Rk are, each independently, hydrogen or a group selected
from a linear or branched, saturated or unsaturated C1-C6
alkyl, a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl; or two adjacent of R4a,
R4b, R4c and R4d, together with the atoms to which they
are attached, form a C5-C7 cycloalkyl, heterocycloalkyl,
aromatic or heteroaromatic ring.

2. The compound according to claim 1, wherein R1 is a
C1-C3 alkyl.

3. The compound according to claim 1, wherein R1 is a substituted or
unsubstituted aryl.

4. The compound according to claim 1, wherein R1 is a phenyl
substituted with one or more Rb, further wherein Rb is selected
from fluorine, chlorine, methoxy, CF3, NHC(O)CH3, and NH2
or two Rb on adjacent carbon atoms form a heterocycloalkyl ring.

5. The compound according to claim 1, wherein R1 is a phenyl
substituted with one or more Rb and Rb is selected from
fluorine, CF3, NHC(O)CH3, and NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring.

6. The compound according to claim 1, wherein R2 is selected from
C1-C3 alkyl, heteroaryl, and aryl.

7. The compound according to claim 1, wherein one or more of R3a,
R3b, R3c, R3d and R3e is C1-C3 alkoxy,
halogen, C1-C3 alkyl, or NRhRi, wherein Rh and
Ri are each independently, hydrogen or C1-C3 alkyl or two
adjacent of R3a, R3b, R3c, R3d, and R3e,
together with the atoms to which they are attached, form a
heterocycloalkyl or heteroaromatic ring.

8. The compound according to claim 1, wherein one of R3a, R3b,
R3c, R3d and R3e is methoxy and the remaining R3a,
R3b, R3c, R3d and R3e are hydrogen.

9. The compound according to claim 1, wherein R4a, R4b,
R4c, and R4d are all hydrogen.

10. The compound according to claim 1, wherein R5 is hydrogen.

11. The compound according to claim 1, wherein the compound is a single
enantiomer.

12. A compound selected from a compound listed in Table 1 or a
pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising a compound claim 1 and at
least one pharmaceutically acceptable carrier or excipient.

14. A method of preventing or treating a cancer and/or a cell
proliferation disorder in a subject, wherein said method comprises the
step of administering to the subject in need thereof, an effective amount
of a compound of claim 1 or a pharmaceutically acceptable salt thereof or
a compound selected from a compound in Table 1, 1A, or 1B or a
pharmaceutically acceptable salt thereof.

15. The method according to claim 14, wherein the cancer and/or cell
proliferation disorder is selected from a disorder of the hematologic
system, lung, colon, pancreas, prostate, skin, ovary, and breast.

16. The method according to claim 15, wherein the medicament is
administered as part of a combination therapy comprising an additional
therapy.

17. A method of preventing or treating a disorder selected from immune
system dysfunction, autoimmune disease, transplant rejection,
inflammatory disorder or disease, and metabolic disorder in a subject,
wherein said method comprises the step of administering to the subject in
need thereof, an effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof or a compound selected from a
compound in Table 1, 1A, or 1B or a pharmaceutically acceptable salt
thereof.

18. The method according to claim 14, wherein the medicament is to be
administered orally, topically or intravenously.

19. The method according to claim 17, wherein the medicament is to be
administered orally, topically or intravenously.

Description:

BACKGROUND OF THE INVENTION

[0001] Tumor development is associated with major metabolic changes. In
the 1920s, Otto Warburg observed that cancer cells have high glucose
consumption and lactate production even in the presence of oxygen (a
process termed aerobic glycolysis). Recent research has demonstrated that
these metabolic differences drive tumor growth. By modulating their
metabolic processes, cancer cells are able to divert sugars, fats and
other energy sources away from energy production to satisfy the ever
growing demands of uncontrolled proliferation.

[0002] Pyruvate Kinase (PK) is a metabolic enzyme that catalyzes the
transfer of a phosphate group from phosphoenol pyruvate to ADP, to
produce pyruvate and ATP during glycolysis. There are four PK
isozymes--the L and the R isozymes are expressed in liver and red blood
cells, respectively; the M1 isozyme is expressed in most adult cells, and
the M2 isoenzyme--an M2 splice variant (PKM2)--is exclusively expressed
during embryonic development and in cancer cells.

[0003] While PKM1 is a constitutively active enzyme, PKM2 undergoes a
transformation from an energy efficient tetrametic form to an `energy
inefficient` dimer form. The main effector that balances the
dimer-tetramer ratio of PKM2 in tissues is fructose 1,6-bisphosphate
(FBP), a glycolysis intermediate product upstream of PKM2.

[0004] PKM2 is a key mediator of the Warburg effect in cancer cells
leading to lower energy production and an abundance of building blocks
for tumor replication and growth. There is thus a need in the art for,
inter alia, modulators of the metabolism of proliferating cells.

SUMMARY OF THE INVENTION

[0005] The invention is directed to compounds that modulate the metabolism
of proliferating cells (e.g., cancer cells or lymphocytes, such as B or T
cells). For example, in some embodiments, compounds of the invention are
useful in the modulation (e.g., activation) of PKM2. Compounds of the
invention are useful as pharmaceutical agents. The compounds may be used
without limitation, for example, as anti-cancer, anti-proliferative,
anti-inflammatory and/or immunosuppressive agents, for treating mammals,
such as for treating humans. Compounds of the invention may be useful for
modulating the metabolism of proliferating cells in a disease or
disorder. Such diseases and disorders include, without limitation,
cancers, inflammatory disorders, autoimmune disorders, immune system
dysfunction, immune disease, metabolic disorders and transplant
rejection. Compounds of the invention may be useful for regulating (e.g.,
activating) a PKM2 involved in a disease or disorder, such as a cancer.

[0006] In one aspect, a compound of the invention includes a compound of
Formula I:

[0008] In one aspect, embodiments of the invention include compounds that
activate PKM2 by at least about 10%, by at least about 20%, by at least
about 25%, by at least about 30%, by at least about 40%, by at least
about 50%, by at least about 60%, by at least about 70%, by at least
about 75%, by at least about 80%, by at least about 90%, or by about 95%
or more.

[0009] In one aspect, a compound of the invention may be used as a
pharmaceutical agent. For example, a compound of the invention is useful
as an anti-cancer, anti-proliferative, anti-inflammatory and/or
immunosuppressive agent, for treating humans and/or animals, such as for
treating humans or other mammals, preferably humans.

[0010] In one aspect, a compound of the invention is used in the
manufacture of a medicament to treat or prevent a disease or disorder
that is modulated by PKM2 activaction. For example, a compound of the
invention may be used in the manufacture of a medicament to be used as an
anti-cancer, anti-proliferative, anti-inflammatory and/or
immunosuppressive agent.

[0011] In one aspect, embodiments of the invention are drawn to methods of
treating or preventing cancers and/or cell proliferation disorders in a
subject by administering a pharmaceutical composition that includes an
effective amount of a compound of the invention or a salt, solvate,
hydrate, or prodrug thereof. For example, the cancer or cell
proliferation disorder is cancer, pre-cancer or a hyperproliferative
disorder. In some embodiments, the foregoing methods are monotherapies
for preventing or treating cancer and/or cell proliferation disorder. In
some embodiments, the foregoing methods are part of a combination therapy
with other therapeutic agents (e.g., a cancer metabolism modulators or a
cytotoxic agent) and/or non-drug therapies (e.g., surgery, immunotherapy
or radiation treatment). In some embodiments of the combination therapy,
the additional therapy is conducted substantially simultaneously or
concurrently with the pharmaceutical composition's administration. In
some embodiments, the administration of the pharmaceutical composition is
conducted prior to the additional therapy of the combination therapy. In
some embodiments, the administration of the pharmaceutical composition is
conducted subsequent to the additional therapy. In some embodiments, the
pharmaceutical composition is administered chronically (e.g., as part of
a maintenance therapy). In some embodiments, the cancer and/or cell
proliferation disorder is a cell proliferative disorder of the
hematologic system (e.g., leukemia or lymphoma). In some embodiments, the
cancer and/or cell proliferation disorder is a cell proliferative
disorder of the lung (e.g., lung cancer). In some embodiments, the cancer
and/or cell proliferation disorder is a cell proliferative disorder of
the colon (e.g., colon cancer). In some embodiments, the cancer and/or
cell proliferation disorder is a cell proliferative disorder of the
pancreas (e.g., pancreatic cancer). In some embodiments, the cancer
and/or cell proliferation disorder is a cell proliferative disorder of
the prostate (e.g., prostate cancer). In some embodiments, the cancer
and/or cell proliferation disorder is a cell proliferative disorder of
the skin (e.g., a skin cancer). In some embodiments, the cancer and/or
cell proliferation disorder is a cell proliferative disorder of the ovary
(e.g., ovarian cancer). In some embodiments, the cancer and/or cell
proliferation disorder is a cell proliferative disorder of the breast
(e.g., breast cancer).

[0012] In certain embodiments, the administration of the compound is
carried out orally, parentally, subcutaneously, intravenously,
intramuscularly, intraperitoneally, by intranasal instillation, by
intracavitary or intravesical instillation, topically, intraarterially,
intralesionally, by metering pump, or by application to mucous membranes.
In some embodiments, the compound is administered with a pharmaceutically
acceptable carrier.

[0013] Another aspect of the invention includes a method of regulating
immune system activity in a subject comprising administering a compound
of the invention or a salt, solvate, hydrate, or prodrug thereof. For
example, modulating immune system activity includes modulating autoimmune
diseases such as transplant rejection (e.g., kidney, heart, lung, liver,
pancreas, skin, host versus graft reaction (HVGR), etc.), rheumatoid
arthritis, and amyotrophic lateral sclerosis. Another aspect of the
invention includes use of a compound of the invention in the manufacture
of a medicament to regulate immune system activity.

[0014] In some embodiments, the administration of the compound is carried
out orally, parentally, subcutaneously, intravenously, intramuscularly,
intraperitoneally, by intranasal instillation, by intracavitary or
intravesical instillation, topically, intraarterially, intralesionally,
by metering pump, or by application to mucous membranes. In some
embodiments, the compound is administered with a pharmaceutically
acceptable carrier. In some embodiments, the compound is administered
before the onset of immune system irregularity. In other embodiments, the
compound is administered after the onset of immune system irregularity.

[0015] In one aspect, embodiments of the invention are drawn to methods of
activating PKM2 by contacting PKM2 with a compound of the invention or a
salt, solvate, hydrate, or prodrug thereof. In some embodiments, PKM2 is
activated by at least about 10%, by at least about 20%, by at least about
25%, by at least about 30%, by at least about 40%, by at least about 50%,
by at least about 60%, by at least about 70%, by at least about 75%, by
at least about 80%, by at least about 90%, or by about 95% or more. In
some embodiments, the PKM2 activated is in a cell, e.g., a human cell.

[0016] A compound of the invention may exist in one or more particular
geometric, optical, enantiomeric, diasteriomeric, epimeric,
stereoisomeric, tautomeric, conformational, or anomeric forms, including
but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and
r-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; (+)
and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms;
synclinal- and anticlinal-forms; α- and β-forms; axial and
equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms;
and combinations thereof, hereinafter collectively referred to as
"isomers" (or "isomeric forms").

[0017] It is contemplated that whenever appropriate, any embodiment of the
invention can be combined with one or more other embodiments of the
invention, even though the embodiments are described under different
aspects of the invention.

[0018] The above description sets forth rather broadly the more important
features of the invention in order that the detailed description thereof
that follows may be understood, and in order that the present
contributions to the art may be better appreciated. Other objects and
features of the invention will become apparent from the following
detailed description considered in conjunction with the examples and
figures.

BRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 shows HPLC chromatograms of
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)eth-
anesulfonamide (Compound 1A). The chromatogram for the starting racemate
is shown in FIG. 1A, and the chromatograms for each of the resolved
individual enantiomers are shown in FIGS. 1B (S-enantiomer) and 1C
(R-enantiomer), respectively.

[0020] FIG. 2 shows HPLC chromatograms of
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-4--
fluorobenzenesulfonamide (Compound 6A). The chromatogram for the starting
racemate is shown in FIG. 2A, and the chromagtograms for each of the
resolved individual enantiomers are shown in FIGS. 2B (R-enantiomer) and
2C (S-enantiomer), respectively.

[0022] FIG. 4 shows the efficacy and safety results using
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)eth-
anesulfonamide (Compound 1A) in a HT-29 xenograft mouse model as described
in Example 10. FIG. 4A is a plot of tumor size at different time points
after tumor inoculation, for a dosing schedule of 400 mg/kg QD, the
vehicle, and a positive control (Irinotecan). FIG. 4B is a plot of Tumor
Growth Inhibition (TGI) as a function of time for two dosing schedules,
i.e., 400 mg/kg QD and 200 mg/kg QD. FIG. 4c is a plot of body weight as
a function of time for the each of the cohorts in the study. FIG. 4D
shows blood pharmacokinetic values for each of the cohorts in the study.

[0024]FIG. 6 shows as a function of concentration of compound a bar graph
of % cells in the indicated stage of the cell cycle (left panel) and a
plot of cell count (right panel) after H1299 cells (a non-small cell lung
carcinoma cell line) were treated for 48 hours with the indicated
concentration of
(S)--N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)pheny-
l)-4-fluorobenzenesulfonamide (Compound 13A).

[0025] FIG. 7 shows a Western blot of PKM2. Recombinant PKM2 was incubated
with various compounds or FBP for 60 min., followed by 0.025%
glutaraldehyde cross-linking (5 min @ 4° C.) before SDS-PAGE
(4-20%) and Western blot analysis with anti-PKM2 antibody (CST). The
tetrameric and monomeric forms of PKM2. Compound 6A was
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-4--
fluorobenzenesulfonamide and Compound 1A was
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)eth-
anesulfonamide.

[0031] The details of one or more embodiments of the invention are set
forth in the accompanying description below. Although any methods and
materials similar or equivalent to those described herein can be used in
the practice or testing of the invention, the preferred methods and
materials are now described. Other features, objects, and advantages of
the invention will be apparent from the description. In the
specification, the singular forms also include the plural unless the
context clearly dictates otherwise. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood by one of ordinary skill in the art to which this
invention belongs. In the case of conflict, the present specification
will control.

[0032] In one aspect, a compound of the invention modulates the metabolism
of proliferating cells (e.g., cancer cells or lymphocytes, such as B or T
cells). Compounds of the invention may be useful as pharmaceutical agents
for modulating the metabolism of proliferating cells in a disease or
disorder. Such diseases and disorders include, without limitation,
cancers, inflammatory disorders, autoimmune disorders, immune system
dysfunction, immune disease, metabolic disorders, and transplant
rejection. For example, the compounds may be useful as anti-cancer,
anti-proliferative, anti-inflammatory and/or immunosuppressive agents,
for treating mammals, such as for treating humans.

[0033] Without wishing to be bound by theory, PKM2 is a key mediator of
the Warburg effect in cancer cells, leading to lower energy production
and an abundance of building blocks for tumor replication and growth.
Thus, it is believed that activating PKM2 may be an important way to
treat or prevent cancers and proliferative diseases. Compounds of the
invention are useful in the activation of PKM2. For example, and without
wishing to be bound by theory, coumpounds according to certain
embodiments of the invention stabilize the active tetrameric form of
PKM2, as shown in FIG. 7. The compounds of the invention are useful as
pharmaceutical agents, for example, as therapeutic agents for treating
humans and animals. The compounds may be used without limitation, for
example, as anti-cancer or other cell proliferation-related disorders.

[0034] In one aspect, the invention provides a compound according to
Formula I:

##STR00002##

or a salt, solvate, hydrate, or prodrug thereof, wherein: W is NRa
or is absent, [0035] wherein Ra is (i) a group selected from the
group consisting of a hydrogen, a linear or branched, saturated or
unsaturated C1-C6 alkyl, C(O)Rc, and a linear or branched,
saturated or unsaturated C1-C6 alkoxy; or (ii) Ra and
R4a together with the atoms to which they are attached, form a five
to seven membered heterocycloalkyl or heteroaromatic ring; R1 is
selected from the group consisting of a hydrogen a linear or branched,
saturated or unsaturated C1-C6 alkyl or heteroalkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl, [0036] wherein said alkyl, heteroalkyl,
cycloalkyl, heterocycloalkyl, aryl or heteroaryl is unsubstituted or
substituted with one or more Rb, [0037] wherein Rb is
independently at each occurrence selected from the group consisting of:
[0038] a) a linear or branched, saturated or unsaturated C1-C6
alkyl, [0039] b) a linear or branched, saturated or unsaturated
C1-C6 haloalkyl, [0040] c) a linear or branched, saturated or
unsaturated C1-C6 alkoxy or aryloxy, [0041] d) a linear or
branched, saturated or unsaturated C1-C6 haloalkoxy, [0042] e)
a linear or branched, saturated or unsaturated C1-C6
alkylsulfonyl, [0043] f) a linear or branched, saturated or unsaturated
C1-C6 thioalkyl or thioaryl, [0044] g) a saturated or
unsaturated C3-C8 cycloalkyl, [0045] h) an aryl, [0046] i) a
heteroaryl, [0047] j) a heterocycloalkyl, [0048] k) hydroxyl, [0049] l)
cyano, [0050] m) amino, [0051] n) nitro, [0052] o) halogen, [0053] p)
CORc, [0054] q) COORc, [0055] r) CONRcRd, [0056] s)
NHCORb, and [0057] t) NRcRd[0058] wherein Rc and
Rd are, each independently, hydrogen or a group selected from a
linear or branched, saturated or unsaturated C1-C6 alkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl; [0059] or wherein two Rb on adjacent
carbon atoms form a heteroaryl ring or heterocycloalkyl ring; [0060]
R2 and R5 are, each independently, selected from hydrogen, a
linear or branched, saturated or unsaturated C1-C6 alkyl or
heteroalkyl, heteroaryl, and aryl, [0061] wherein said alkyl,
heteroalkyl, heteroaryl, or aryl is unsubstituted or substituted with one
or more Re, [0062] wherein Re is independently at each
occurrence selected from the group consisting of CORf, COORf,
CONRfRg, NHCORf, and NRfRg, [0063] wherein
Rf and Rg are, each independently, hydrogen or a group selected
from a linear or branched, saturated or unsaturated C1-C6
alkyl, a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl; R3a, R3b, R3c,
R3d and R3e are, each independently, selected from: [0064]
a) hydrogen [0065] b) a linear or branched, saturated or unsaturated
C1-C6 alkyl, [0066] c) a linear or branched, saturated or
unsaturated C1-C6 haloalkyl, [0067] d) a linear or branched,
saturated or unsaturated C1-C6 alkoxy or aryloxy, [0068] e) a
linear or branched, saturated or unsaturated C1-C6 haloalkoxy,
[0069] f) a linear or branched, saturated or unsaturated C1-C6
alkylsulfonyl, [0070] g) a linear or branched, saturated or unsaturated
C1-C6 thioalkyl or thioaryl, [0071] h) a saturated or
unsaturated C3-C8 cycloalkyl, [0072] i) an aryl, [0073] j) a
heteroaryl, [0074] k) a heterocycloalkyl, [0075] l) hydroxyl, [0076] m)
cyano, [0077] n) amino, [0078] o) nitro, [0079] p) halogen, [0080] q)
CORh, [0081] r) COORh, [0082] s) CONRhRi, [0083] t)
NHCORh, or [0084] u) NRhRi[0085] wherein Rh and
Ri are, each independently, hydrogen or a group selected from a
linear or branched, saturated or unsaturated C1-C6 alkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl;

[0086] or [0087] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring; R4b, R4c and R4d, and when R4a does not form a
five to seven membered ring with Ra, R4a, are each
independently, selected from: [0088] a) hydrogen [0089] b) a linear or
branched, saturated or unsaturated C1-C6 alkyl, [0090] c) a
linear or branched, saturated or unsaturated C1-C6 haloalkyl,
[0091] d) a linear or branched, saturated or unsaturated C1-C6
alkoxy or aryloxy, [0092] e) a linear or branched, saturated or
unsaturated C1-C6 haloalkoxy, [0093] f) a linear or branched,
saturated or unsaturated C1-C6 alkylsulfonyl, [0094] g) a
linear or branched, saturated or unsaturated C1-C6 thioalkyl or
thioaryl, [0095] h) a saturated or unsaturated C3-C8
cycloalkyl, [0096] i) an aryl, [0097] j) a heteroaryl, [0098] k) a
heterocycloalkyl, [0099] l) hydroxyl, [0100] m) cyano, [0101] n) amino,
[0102] o) nitro, [0103] p) halogen, [0104] q) CORj, [0105] r)
COORj, [0106] s) CONRjRk, [0107] t) NHCORj, and
[0108] u) NRjRk[0109] wherein Rj and Rk are, each
independently, hydrogen or a group selected from a linear or branched,
saturated or unsaturated C1-C6 alkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl;

[0110] or [0111] two adjacent of R4a, R4b, R4c and
R4d, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0112] In one aspect, compounds according to embodiments of the invention
include a compounds of Formula I or a salt, solvate, hydrate or prodrug
thereof wherein:

W is NRa or is absent, [0113] wherein Ra is (i) a group
selected from the group consisting of a hydrogen, a linear or branched,
saturated or unsaturated C1-C6 alkyl, and a linear or branched,
saturated or unsaturated C1-C6 alkoxy; or (ii) Ra and
R4a together with the atoms to which they are attached, form a five
to seven membered heterocycloalkyl or heteroaromatic ring; R1 is
selected from the group consisting of a hydrogen a linear or branched,
saturated or unsaturated C1-C6 alkyl or heteroalkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl,

[0114] wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl
or heteroaryl is unsubstituted or substituted with one or more Rb,

[0162] or [0163] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring; R4b, R4c and R4d, and when R4a, does not form a
five to seven membered ring with Ra, R4a, are, each
independently, selected from: [0164] a) hydrogen [0165] b) a linear or
branched, saturated or unsaturated C1-C6 alkyl, [0166] c) a
linear or branched, saturated or unsaturated C1-C6 haloalkyl,
[0167] d) a linear or branched, saturated or unsaturated C1-C6
alkoxy or aryloxy, [0168] e) a linear or branched, saturated or
unsaturated C1-C6 haloalkoxy, [0169] f) a linear or branched,
saturated or unsaturated C1-C6 alkylsulfonyl, [0170] g) a
linear or branched, saturated or unsaturated C1-C6 thioalkyl or
thioaryl, [0171] h) a saturated or unsaturated C3-C8
cycloalkyl, [0172] i) an aryl, [0173] j) a heteroaryl, [0174] k) a
heterocycloalkyl, [0175] l) hydroxyl, [0176] m) cyano, [0177] n) amino,
[0178] o) nitro, [0179] p) halogen, [0180] q) CORj, [0181] r)
COORj, [0182] s) CONRjRk, [0183] t) NHCORj, and
[0184] u) NRjRk[0185] wherein Rj and Rk are, each
independently, hydrogen or a group selected from a linear or branched,
saturated or unsaturated C1-C6 alkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl;

[0186] or [0187] two adjacent of R4a, R4b, R4c and
R4d, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0188] In one aspect, embodiments of the invention include a compound of
Formula Ia:

##STR00003##

or a salt, solvate, hydrate, or prodrug thereof.

[0189] In one aspect, embodiments of the invention include a compound of
Formula Ib:

##STR00004##

[0190] In one aspect, embodiments of the invention include a mixture of a
compound of Formula Ia and a compound of Formula Ib.

[0191] Some embodiments of classes of Formulae I, Ia, and Ib are discussed
below.

[0192] In some embodiments, W is absent. In some embodiments, W is NH. In
some embodiments, W is NRa, where Ra is not a hydrogen. In some
embodiments, Ra and R4a together with the atoms to which they
are attached, form a five to seven membered heterocycloalkyl. For
example, Ra and R4a together with the atoms to which they are
attached, form a five membered heterocycloalkyl ring, where Ra and
R4a collectively are (CH2)2.

[0193] In some embodiments, R1 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0194] In some embodiments, R1 is an unsubstituted or substituted,
aryl or heteroaryl group. For example, R1 is a substituted or
unsubstituted benzyl group. In some embodiments, the aryl or heteroaryl
is substituted with one or more halogen (e.g., fluorine). In some cases,
the aryl or heteroaryl may suibtably be substituted with a single halogen
(e.g., R1 is 4-fluorophenyl). In some cases, the aryl or heteroaryl
may suibtably be substituted with two or more halogen (e.g., R1 is
2,6-difluorophenyl). In some embodiments, the aryl or heteroaryl is
substituted with one or more alkoxy (e.g., methoxy). In some cases, the
aryl or heteroaryl may suibtably be substituted with a single alkoxy. In
some cases, the aryl or heteroaryl may suibtably be substituted with two
or more alkoxy. In some embodiments, the aryl or heteroaryl is
substituted with two adjacent substituents that together with the atoms
to which they are attached, form a five to seven membered ring. In some
embodiments, the ring is a six membered ring. In some embodiments, the
ring is a five membered ring. In some embodiments, the two adjacent
substituents, together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)p--O--, where p is 1 to 3 (e.g., 2).

[0195] In some embodiments, R2 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0196] In some embodiments, R3a, R3b, R3c, R3d and
R3e are all hydrogen. In some embodiments, one or more of R3a,
R3b, R3c, R3d and R3e are not hydrogen. In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is not hydrogen, and the remaining values are hydrogen. In some
embodiments, one or more of R3a, R3b, R3c, R3d and
R3e are halogen (e.g., fluorine). In some embodiments, only one of
R3a, R3b, R3c, R3d and R3e is halogen (e.g.,
either R3a or R3c is fluorine), and the remaining values are
hydrogen. In some embodiments, one or more of R3a, R3b,
R3c, R3d and R3e are alkoxy (e.g., methoxy). In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is alkoxy (e.g., R3e is methoxy), and the remaining values
are hydrogen. In some embodiments, two or more of R3a, R3b,
R3c, R3d and R3e is alkoxy (e.g., methoxy), and the
remaining values are hydrogen.

[0197] In some embodiments, two adjacent of R3a, R3b, R3c,
R3d and R3e, together with the atoms to which they are
attached, form a five to seven membered ring. In some embodiments, the
ring is a six membered ring. In some embodiments, the ring is a five
membered ring. In some embodiments, the two adjacent substituents,
together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)q--O--, where q is 1 to 3 (e.g., 1 or 2).

[0198] In some embodiments, R4a, R4b, r4c and R4d are
all hydrogen. In some embodiments, one or more of R4a, R4b,
R3c and R4d are not hydrogen. In some embodiments, only one of
R4a, R4b, R4c and R4d is not hydrogen, and the
remaining values are hydrogen.

[0199] In some embodiments, R5 is hydrogen. In some embodiments,
R5 is not hydrogen.

[0200] In one aspect, the invention provides a compound of Formula II:

##STR00005##

or a salt, solvate, hydrate, or prodrug thereof: W is NRa or is
absent, [0201] wherein Ra is (i) a group selected from the group
consisting of a hydrogen, a linear or branched, saturated or unsaturated
C1-C6 alkyl, C(O)Rc, and a linear or branched, saturated
or unsaturated C1-C6 alkoxy; or (ii) Ra and R4a
together with the atoms to which they are attached, form a five to seven
membered heterocycloalkyl or heteroaromatic ring; R1 is selected
from the group consisting of a hydrogen a linear or branched, saturated
or unsaturated C1-C6 alkyl or heteroalkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl,

[0202] wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl
or heteroaryl is unsubstituted or substituted with one or more Rb,

[0251] or [0252] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring; R4b, R4c and R4d, and when Ra4 does not form a
five to seven membered ring with Ra, R4a, are, each
independently, selected from: [0253] a) hydrogen [0254] b) a linear or
branched, saturated or unsaturated C1-C6 alkyl, [0255] c) a
linear or branched, saturated or unsaturated C1-C6 haloalkyl,
[0256] d) a linear or branched, saturated or unsaturated C1-C6
alkoxy or aryloxy, [0257] e) a linear or branched, saturated or
unsaturated C1-C6 haloalkoxy, [0258] f) a linear or branched,
saturated or unsaturated C1-C6 alkylsulfonyl, [0259] g) a
linear or branched, saturated or unsaturated C1-C6 thioalkyl or
thioaryl, [0260] h) a saturated or unsaturated C3-C8
cycloalkyl, [0261] i) an aryl, [0262] j) a heteroaryl, [0263] k) a
heterocycloalkyl, [0264] 1) hydroxyl, [0265] m) cyano, [0266] n) amino,
[0267] o) nitro, [0268] p) halogen, [0269] q) CORj, [0270] r)
COORj, [0271] s) CONRjRk, [0272] t) NHCORj, and
[0273] u) NRjRk[0274] wherein Rj and Rk are, each
independently, hydrogen or a group selected from a linear or branched,
saturated or unsaturated C1-C6 alkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl;

[0275] or [0276] two adjacent of R4a, R4b, R4c, and
R4d, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0277] In one aspect, compounds according to embodiments of the invention
include a compound of Formula II, wherein:

W is NRa or is absent, [0278] wherein Ra is (i) a group
selected from the group consisting of a hydrogen, a linear or branched,
saturated or unsaturated C1-C6 alkyl, and a linear or branched,
saturated or unsaturated C1-C6 alkoxy; or (ii) Ra and
R4a together with the atoms to which they are attached, form a five
to seven membered heterocycloalkyl or heteroaromatic ring; R1 is
selected from the group consisting of a hydrogen a linear or branched,
saturated or unsaturated C1-C6 alkyl or heteroalkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl,

[0279] wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl
or heteroaryl is unsubstituted or substituted with one or more Rb,

[0302] wherein said alkyl or heteroalkyl is unsubstituted or substituted
with one or more Re, [0303] wherein Re is independently at
each occurrence selected from the group consisting of CORf,
COORf, CONRfRg, NHCORf, and NRfRg, [0304]
wherein Rf and Rg are, each independently, hydrogen or a group
selected from a linear or branched, saturated or unsaturated
C1-C6 alkyl, a saturated or unsaturated C3-C8
cycloalkyl or heterocycloalkyl, an aryl and a heteroaryl; R3a,
R3b, R3c, R3d and R3e are, each independently,
selected from: [0305] a) hydrogen [0306] b) a linear or branched,
saturated or unsaturated C1-C6 alkyl, [0307] c) a linear or
branched, saturated or unsaturated C1-C6 haloalkyl, [0308] d) a
linear or branched, saturated or unsaturated C1-C6 alkoxy or
aryloxy, [0309] e) a linear or branched, saturated or unsaturated
C1-C6 haloalkoxy, [0310] f) a linear or branched, saturated or
unsaturated C1-C6 alkylsulfonyl, [0311] g) a linear or
branched, saturated or unsaturated C1-C6 thioalkyl or thioaryl,
[0312] h) a saturated or unsaturated C3-C8 cycloalkyl, [0313]
i) an aryl, [0314] j) a heteroaryl, [0315] k) a heterocycloalkyl, [0316]
l) hydroxyl, [0317] m) cyano, [0318] n) amino, [0319] o) nitro, [0320] p)
halogen, [0321] q) CORh, [0322] r) COORh, [0323] s)
CONRhRi, [0324] t) NHCORh, and [0325] u) NRhRi[0326] wherein Rh and Ri are, each independently, hydrogen or a
group selected from a linear or branched, saturated or unsaturated
C1-C6 alkyl, a saturated or unsaturated C3-C8
cycloalkyl or heterocycloalkyl, an aryl and a heteroaryl;

[0327] or [0328] two adjacent of R3a, R3b, R3c, R3d,
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring; R4b, R4c and R4d, and when R4a does not form a
five to seven membered ring with Ra, R4a, are, each
independently, selected from: [0329] a) hydrogen [0330] b) a linear or
branched, saturated or unsaturated C1-C6 alkyl, [0331] c) a
linear or branched, saturated or unsaturated C1-C6 haloalkyl,
[0332] d) a linear or branched, saturated or unsaturated C1-C6
alkoxy or aryloxy, [0333] e) a linear or branched, saturated or
unsaturated C1-C6 haloalkoxy, [0334] f) a linear or branched,
saturated or unsaturated C1-C6 alkylsulfonyl, [0335] g) a
linear or branched, saturated or unsaturated C1-C6 thioalkyl or
thioaryl, [0336] h) a saturated or unsaturated C3-C8
cycloalkyl, [0337] i) an aryl, [0338] j) a heteroaryl, [0339] k) a
heterocycloalkyl, [0340] l) hydroxyl, [0341] m) cyano, [0342] n) amino,
[0343] o) nitro, [0344] p) halogen, [0345] q) CORj, [0346] r)
COORj, [0347] s) CONRkRk, [0348] t) NHCORj, and
[0349] u) NRjRk[0350] wherein Rj and Rk are, each
independently, hydrogen or a group selected from a linear or branched,
saturated or unsaturated C1-C6 alkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl;

[0351] or [0352] two adjacent of R4a, R4b, R4c and
R4d, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0353] In one aspect, embodiments of the invention include a compound of
Formula IIa:

##STR00006##

or a salt, solvate, hydrate, or prodrug thereof.

[0354] In one aspect, embodiments of the invention include a compound of
Formula IIb:

##STR00007##

or a salt, solvate, hydrate, or prodrug thereof.

[0355] In one aspect, embodiments of the invention include a mixture of a
compound of Formula IIa and a compound of Formula IIb.

[0356] Some embodiments of classes of formulae II, IIa, or IIb are
described below.

[0357] In some embodiments, W is absent. In some embodiments, W is NH. In
some embodiments, W is NRa, where Ra is not hydrogen. In some
embodiments, Ra and R4a together with the atoms to which they
are attached, form a five to seven membered heterocycloalkyl. For
example, Ra and R4a together with the atoms to which they are
attached, form a five membered heterocycloalkyl ring, where Ra and
R4a collectively are (CH2)2.

[0358] In some embodiments, R1 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0359] In some embodiments, R1 is an unsubstituted or substituted
aryl or heteroaryl group. For example, R1 is a substituted or
unsubstituted benzyl group. In some embodiments, the aryl or heteroaryl
is substituted with one or more halogen (e.g., fluorine). In some cases,
the aryl or heteroaryl may suibtably be substituted with a single halogen
(e.g., R1 is 4-fluorophenyl). In some cases, the aryl or heteroaryl
may suibtably be substituted with two or more halogen (e.g., R1 is
2,6-difluorophenyl). In some embodiments, the aryl or heteroaryl is
substituted with one or more alkoxy (e.g., methoxy). In some cases, the
aryl or heteroaryl may suibtably be substituted with a single alkoxy. In
some cases, the aryl or heteroaryl may suibtably be substituted with two
or more alkoxy. In some embodiments, the aryl or heteroaryl is
substituted with two adjacent substituents that together with the atoms
to which they are attached, form a five to seven membered ring. In some
embodiments, the ring is a six membered ring. In some embodiments, the
ring is a five membered ring. In some embodiments, the two adjacent
substituents, together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)p--O--, where p is 1 to 3 (e.g., 2).

[0360] In some embodiments, R2 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0361] In some embodiments, R3a, R3b, R3c, R3d and
R3e are all hydrogen. In some embodiments, one or more of R3a,
R3b, R3c, R3d and R3e are not hydrogen. In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is not hydrogen, and the remaining values are hydrogen. In some
embodiments, one or more of R3a, R3b, R3c, R3d and
R3e are halogen (e.g., fluorine). In some embodiments, only one of
R3a, R3b, R3c, R3d and R3e is halogen (e.g.,
either R3a or R3c is fluorine), and the remaining values are
hydrogen. In some embodiments, one or more of R3a, R3b,
R3c, R3d and R3e are alkoxy (e.g., methoxy). In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is alkoxy (e.g., R3e is methoxy), and the remaining values
are hydrogen. In some embodiments, two or more of R3a, R3b,
R3c, R3d and R3e is alkoxy (e.g., methoxy), and the
remaining values are hydrogen.

[0362] In some embodiments, two adjacent of R3a, R3b, R3c,
R3d and R3e, together with the atoms to which they are
attached, form a five to seven membered ring. In some embodiments, the
ring is a six membered ring. In some embodiments, the ring is a five
membered ring. In some embodiments, the two adjacent substituents,
together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)q--O--, where q is 1 to 3 (e.g., 1 or 2).

[0363] In some embodiments, R4a, R4b, R4c and R4d are
all hydrogen. In some embodiments, one or more of R4a, R4b,
R4c and R4e are not hydrogen. In some embodiments, only one of
R4a, R4b, R4c and R4d is not hydrogen, and the
remaining values are hydrogen.

[0364] In one aspect, the invention provides a compound according to
Formula III:

##STR00008##

or a salt, solvate, hydrate or prodrug, wherein: R1 is selected from
the group consisting of a hydrogen, a linear or branched, saturated or
unsaturated C1-C6 alkyl or heteroalkyl, a saturated or
unsaturated C3-C8 cycloalkyl or heterocycloalkyl, an aryl and a
heteroaryl,

[0365] wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl is unsubstituted or substituted with one or more Rb,

[0414] or [0415] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring; R4a, R4b, R4c and R4d are, each independently,
selected from: [0416] a) hydrogen [0417] b) a linear or branched,
saturated or unsaturated C1-C6 alkyl, [0418] c) a linear or
branched, saturated or unsaturated C1-C6 haloalkyl, [0419] d) a
linear or branched, saturated or unsaturated C1-C6 alkoxy or
aryloxy, [0420] e) a linear or branched, saturated or unsaturated
C1-C6 haloalkoxy, [0421] f) a linear or branched, saturated or
unsaturated C1-C6 alkylsulfonyl, [0422] g) a linear or
branched, saturated or unsaturated C1-C6 thioalkyl or thioaryl,
[0423] h) a saturated or unsaturated C3-C8 cycloalkyl, [0424]
i) an aryl, [0425] j) a heteroaryl, [0426] k) a heterocycloalkyl, [0427]
l) hydroxyl, [0428] m) cyano, [0429] n) amino, [0430] o) nitro, [0431] p)
halogen, [0432] q) CORj, [0433] r) COORj, [0434] s)
CONRjRh, [0435] t) NHCORj, and [0436] u) NRjRk[0437] wherein Rj and Rk are, each independently, hydrogen or a
group selected from a linear or branched, saturated or unsaturated
C1-C6 alkyl, a saturated or unsaturated C3-C8
cycloalkyl or heterocycloalkyl, an aryl and a heteroaryl; [0438] or
[0439] two adjacent of R4a, R4b, R3c and R4d,
together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0440] In one aspect, compounds according to embodiments of the invention
include a compound of Formula III, wherein:

R1 is selected from the group consisting of a hydrogen a linear or
branched, saturated or unsaturated C1-C6 alkyl or heteroalkyl,
a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl,

[0441] wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl
or heteroaryl is unsubstituted or substituted with one or more Rb,

[0513] or [0514] two adjacent of R4a, R4b, R4c and
R4d, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0515] In one aspect, embodiments of the invention include a compound of
Formula Ma:

##STR00009##

[0516] In one aspect, embodiments of the invention include a compound of
Formula Mb:

##STR00010##

[0517] In one aspect, embodiments of the invention include a mixture of a
compound of Formula IIIa and a compound of Formula Mb.

[0518] Some embodiments of classes of formulae III, IIIa, or IIIb are
described below.

[0519] In some embodiments, R1 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0520] In some embodiments, R1 is an unsubstituted or substituted
aryl or heteroaryl group. For example, R1 is a substituted or
unsubstituted benzyl group. In some embodiments, the aryl or heteroaryl
is substituted with one or more halogen (e.g., fluorine). In some cases,
the aryl or heteroaryl may suibtably be substituted with a single halogen
(e.g., R1 is 4-fluorophenyl). In some cases, the aryl or heteroaryl
may suibtably be substituted with two or more halogen (e.g., R1 is
2,6-difluorophenyl). In some embodiments, the aryl or heteroaryl is
substituted with one or more alkoxy (e.g., methoxy). In some cases, the
aryl or heteroaryl may suibtably be substituted with a single alkoxy. In
some cases, the aryl or heteroaryl may suibtably be substituted with two
or more alkoxy. In some embodiments, the aryl or heteroaryl is
substituted with two adjacent substituents that together with the atoms
to which they are attached, form a five to seven membered ring. In some
embodiments, the ring is a six membered ring. In some embodiments, the
ring is a five membered ring. In some embodiments, the two adjacent
substituents, together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)p--O--, where p is 1 to 3 (e.g., 2).

[0521] In some embodiments, R2 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0522] In some embodiments, R3a, R3b, R3c, R3d and
R3e are all hydrogen. In some embodiments, one or more of R3a,
R3b, R3c, R3d and R3e are not hydrogen. In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is not hydrogen, and the remaining values are hydrogen. In some
embodiments, one or more of R3a, R3b, R3c, R3d and
R3e are halogen (e.g., fluorine). In some embodiments, only one of
R3a, R3b, R3c, R3d and R3e is halogen (e.g.,
either R3a or R3e is fluorine), and the remaining values are
hydrogen. In some embodiments, one or more of R3a, R3b,
R3c, R3d and R3e are alkoxy (e.g., methoxy). In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is alkoxy (e.g., R3c is methoxy), and the remaining values
are hydrogen. In some embodiments, two or more of R3a, R3b,
R3c, R3d and R3e is alkoxy (e.g., methoxy), and the
remaining values are hydrogen.

[0523] In some embodiments, two adjacent of R3a, R3b, R3c,
R3d and R3e, together with the atoms to which they are
attached, form a five to seven membered ring. In some embodiments, the
ring is a six membered ring. In some embodiments, the ring is a five
membered ring. In some embodiments, the two adjacent substituents,
together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)q--O--, where q is 1 to 3 (e.g., 1 or 2).

[0524] In some embodiments, R4a, R4b, R4c and R4d are
all hydrogen. In some embodiments, one or more of R4a, R3b,
R4c and R4d are not hydrogen. In some embodiments, only one of
R4a, R4b, R4c and R4d is not hydrogen, and the
remaining values are hydrogen.

[0525] In one aspect, the invention provides a compound according to
Formula IV:

##STR00011##

or a salt, solvate, hydrate, or prodrug thereof, wherein: R1 is
selected from the group consisting of a hydrogen a linear or branched,
saturated or unsaturated C1-C6 alkyl or heteroalkyl, a
saturated or unsaturated C3-C8 cycloalkyl or heterocycloalkyl,
an aryl and a heteroaryl,

[0526] wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or
heteroaryl is unsubstituted or substituted with one or more Rb,

[0575] or [0576] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0577] In one aspect, compounds according to embodiments of the invention
include a compound of Formula IV, wherein:

R1 is selected from the group consisting of a hydrogen a linear or
branched, saturated or unsaturated C1-C6 alkyl or heteroalkyl,
a saturated or unsaturated C3-C8 cycloalkyl or
heterocycloalkyl, an aryl and a heteroaryl,

[0578] wherein said alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl
or heteroaryl is unsubstituted or substituted with one or more Rh,

[0626] or [0627] two adjacent of R3a, R3b, R3c, R3d
and R3e, together with the atoms to which they are attached, form a
C5-C7 cycloalkyl, heterocycloalkyl, aromatic or heteroaromatic
ring.

[0628] In one aspect, embodiments of the invention include a compound of
Formula IVa:

##STR00012##

or a salt, solvate, hydrate, or prodrug thereof.

[0629] In one aspect, embodiments of the invention include a compound of
Formula IVb:

##STR00013##

or a salt, solvate, hydrate, or prodrug thereof.

[0630] In one aspect, embodiments of the invention include a mixture of a
compound of Formula IVa and a compound of Formula IVb.

[0631] Some embodiments of preferred classes of formulae IV, IVa, and IVb
are described below.

[0632] In some embodiments, R1 is C1-C6 alkyl, such as a
C1-C3 alkyl (e.g., methyl or ethyl).

[0633] In some embodiments, R1 is an unsubstituted or substituted
aryl or heteroaryl group. For example, R1 is a substituted or
unsubstituted benzyl group. In some embodiments, the aryl or heteroaryl
is substituted with one or more halogen (e.g., fluorine). In some cases,
the aryl or heteroaryl may suibtably be substituted with a single halogen
(e.g., R1 is 4-fluorophenyl). In some cases, the aryl or heteroaryl
may suibtably be substituted with two or more halogen (e.g., R1 is
2,6-difluorophenyl). In some embodiments, the aryl or heteroaryl is
substituted with one or more alkoxy (e.g., methoxy). In some cases, the
aryl or heteroaryl may suibtably be substituted with a single alkoxy. In
some cases, the aryl or heteroaryl may suibtably be substituted with two
or more alkoxy. In some embodiments, the aryl or heteroaryl is
substituted with two adjacent substituents that together with the atoms
to which they are attached, form a five to seven membered ring. In some
embodiments, the ring is a six membered ring. In some embodiments, the
ring is a five membered ring. In some embodiments, the two adjacent
substituents, together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)p--O--, where p is 1 to 3 (e.g., 2).

[0634] In some embodiments, R2 is C1-C6 alkyl, such as
C1-C3 alkyl (e.g., methyl or ethyl).

[0635] In some embodiments, R3a, R3b, R3c, R3d and
R3e are all hydrogen. In some embodiments, one or more of R3a,
R3b, R3c, R3d and R3e are not hydrogen. In some
embodiments, only one of R3a, R3b, R3c, R3d and
R3e is not hydrogen, and the remainding values are hydrogen.

[0636] In some embodiments, one or more of R3a, R3b, R3c,
R3d and R3e are halogen (e.g., fluorine). In some embodiments,
only one of R3a, R3b, R3c, R3d and R3e is
halogen (e.g., either R3a or R3c is fluorine), and the
remaining values are hydrogen. In some embodiments, one or more of
R3a, R3b, R3c, R3d and R3e are alkoxy (e.g.,
methoxy). In some embodiments, only one of R3a, R3b, R3c,
R3d and R3c is alkoxy (e.g., R3c is methoxy), and the
remaining values are hydrogen. In some embodiments, two or more of
R3a, R3b, R3c, R3d and R3e is alkoxy (e.g.,
methoxy), and the remaining values are hydrogen.

[0637] In some embodiments, two adjacent of R3a, R3b, R3c,
R3d and R3e, together with the atoms to which they are
attached, form a five to seven membered ring. In some embodiments, the
ring is a six membered ring. In some embodiments, the ring is a five
membered ring. In some embodiments, the two adjacent substituents,
together with the atoms to which they are attached, form a
heterocycloalkyl ring, where the two adjacent substituents collectively
are --O--(CH2)q--O--, where q is 1 to 3 (e.g., 1 or 2).

[0638] In one aspect, the invention provides a compound of Formula V:

##STR00014##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3a, R3b, R3c, R3d, R3e, and Rb
are as described for Formula I and t is 0, 1, 2, 3, 4 or 5.

[0639] In one aspect, embodiments of the invention include a compound of
Formula Va:

##STR00015##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3a, R3b, R3c, R3d, R3e, and Rb
are as described for Formula I and t is 0, 1, 2, 3, 4 or 5.

[0640] In one aspect, embodiments of the invention include a compound of
Formula Vb:

##STR00016##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3a, R3b, R3c, R3d, R3e, and Rb
are as described for Formula I and t is 0, 1, 2, 3, 4 or 5.

[0641] In one aspect, the invention provides a compound of Formula VI:

##STR00017##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3b, R3c, and Rb are as described for Formula I
and t is 0, 1, 2, 3, 4 or 5.

[0642] In one aspect, embodiments of the invention include a compound of
Formula VIa:

##STR00018##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3b, R3c, and Rb are as described for Formula I
and t is 0, 1, 2, 3, 4 or 5.

[0643] In one aspect, embodiments of the invention include a compound of
Formula VIb:

##STR00019##

or a salt, solvate, hydrate, or prodrug thereof, wherein Ra,
R2, R3b, R3c, and Rb are as described for Formula I
and t is 0, 1, 2, 3, 4 or 5.

[0644] Some embodiments of preferred classes are described below for
formulae of the invention.

[0645] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a C1-C3 alkyl. In one aspect, embodiments of
the invention include a compound of Formulae I, Ia, Ib, II, IIa, IIb,
III, IIIa, IIIb, IV, IVa, or IVb, wherein R1 is methyl. In one
aspect, embodiments of the invention include a compound of Formulae I,
Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, wherein R1
is ethyl.

[0646] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb),
wherein R1 is a substituted or unsubstituted aryl. In one aspect,
embodiments of the invention include a compound of Formulae I, Ia, Ib,
II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, wherein R1 is aryl
substituted with one or more halogen. In one aspect, embodiments of the
invention include a compound of Formulae I, Ia, Ib, II, IIa, IIb, III,
IIIa, IIIb, IV, IVa, or IVb, wherein R1 is an unsubstituted phenyl.
In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one Rb.

[0652] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more Rb and
Rb is selected from halogen, C1-C3 alkoxy, CF3,
NHC(O)Rc, and NRcRd or two Rb on adjacent carbon
atoms form a heterocycloalkyl ring and Rc and Rd are, each
independently, hydrogen or linear or branched, saturated or unsaturated
C1-C3 alkyl.

[0653] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more Rb and
Rb is selected from fluorine, chlorine, methoxy, CF3,
NHC(O)CH3, and NH2 or two Rb on adjacent carbon atoms form
a heterocycloalkyl ring.

[0654] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more Rb and
Rb is selected from fluorine, CF3, NHC(O)CH3, and NH2
or two Rb on adjacent carbon atoms form a heterocycloalkyl ring.

[0655] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more fluorine. In one
aspect, embodiments of the invention include a compound of Formulae I,
Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, wherein R1
is a phenyl substituted with one fluorine. In one aspect, embodiments of
the invention include a compound of Formulae I, Ia, Ib, II, IIa, IIb,
III, IIIa, IIIb, IV, IVa, or IVb, wherein R1 is a phenyl substituted
with two fluorine.

[0656] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more methoxy. In one
aspect, embodiments of the invention include a compound of Formulae I,
Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, wherein R1
is a phenyl substituted with one methoxy.

[0657] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted with one or more CF3. In one
aspect, embodiments of the invention include a compound of Formulae I,
Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb, wherein R1
is a phenyl substituted with one CF3.

[0658] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb,
wherein R1 is a phenyl substituted two Rb to form the
heterocycloalkyl ring:

##STR00024##

[0659] In one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb), wherein Rb is selected from
halogen, C1-C3 alkoxy, CF3, NHC(O)Rc, and
NRcRd or two Rb on adjacent carbon atoms form a
heterocycloalkyl ring and Rc and Rd are, each independently,
hydrogen or linear or branched, saturated or unsaturated C1-C3
alkyl.

[0660] In one aspect, embodiments of the invention include a compound of
FIn one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb), wherein Rb is selected from
fluorine, chlorine, methoxy, CF3, NHC(O)CH3, and NH2 or
two Rb on adjacent carbon atoms form a heterocycloalkyl ring.

[0661] In one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb, wherein Rb is selected from
fluorine, CF3, NHC(O)CH3, and NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring.

[0662] In one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb, wherein Rb is fluorine.

[0663] In one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb, wherein Rb is methoxy.

[0664] In one aspect, embodiments of the invention include a compound of
Formulae V, Va, Vb, VI, VIa, or VIb, wherein Rb is CF3.

[0668] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein one of R3a, R3b, R3c, R3d and R3e
is not hydrogen and the remaining R3a, R3b, R3c, R3d
and R3e are hydrogen. In one aspect, embodiments of the invention
include a compound of Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, TIM,
IV, IVa, IVb, V, Va, or Vb, wherein R3c is not hydrogen. In one
aspect, embodiments of the invention include a compound of Formulae I,
Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb),
wherein two of R3a, R3b, R3c, R3d and R3e are
not hydrogen and the remaining R3a, R3b, R3c, R3d,
and R3e are hydrogen. In one aspect, embodiments of the invention
include a compound of Formulae I, Ia, Ib, II, IIa, IIb, III, TIM, TIM,
IV, IVa, IVb, V, Va, or Vb, wherein R3b and R3c are not
hydrogen and the remaining R3a, R3d and R3e are hydrogen.
In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, TIM, IV, IVa, IVb, V, Va, or
Vb, wherein three of R3a, R3b, R3c, R3d and R3e
are not hydrogen and the remaining R3a, R3b, R3c, R3d
and R3e are hydrogen.

[0669] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein one or more of R3a, R3b, R3c, R3d and
R3e is C1-C3 alkoxy, halogen, C1-C3 alkyl, or
NRhRi, wherein Rh and TV are each independently, hydrogen
or C1-C3 alkyl or two adjacent of R3a, R3b, R3c,
R3d, and R3e, together with the atoms to which they are
attached, form a heterocycloalkyl or heteroaromatic ring.

[0670] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein one or more of R3a, R3b, R3c, R3d and
R3e is methoxy, fluorine, chlorine, methyl, or NH2.

[0671] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, TIM, TIM, IV, IVa, IVb, V, Va, or
Vb, wherein one of R3a, R3b, R3c, R3d and R3e is
methoxy and the remaining R3a, R3b, R3c, R3d and
R3e are hydrogen.

[0672] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein two adjacent of R3a, R3b, R3c, R3d,
and R3e, together with the atoms to which they are attached, form a
ring selected from:

##STR00025##

[0673] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein two adjacent of R3b and R3c together with the
atoms to which they are attached, form a ring selected from:

##STR00026##

[0674] In one aspect, embodiments of the invention include a compound of
Formulae VI, VIa, or VIb), wherein one of R3b or R3c is
C1-C3 alkoxy, halogen, C1-C3 alkyl, or
NRhRi, wherein Rh and Ri are each independently,
hydrogen or C1-C3 alkyl and the remaining R3b or R3c
is hydrogen.

[0675] In one aspect, embodiments of the invention include a compound of
Formulae VI, VIa, or VIb, wherein one of R3b or R3c is methoxy,
fluorine, chlorine, methyl, or NH2 and the remaining R3b or
R3c is hydrogen.

[0676] In one aspect, embodiments of the invention include a compound of
Formulae I, R3b, R3c, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb,
IV, IVa, IVb, V, Va, or Vb, wherein one or more of R3a, R3d and
R3e is C1-C3 alkoxy.

[0677] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va,
or Vb, wherein one or more of R3a, R3b, R3c, R3d and
R3e is methoxy.

[0678] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, Ib, II, IIa, IIb, III, IIIa, or IIIb, wherein R4a,
R4b, R4c, and R4d are each hydrogen.

[0679] In one aspect, embodiments of the invention include a compound of
Formulae I, Ia, or Ib, wherein R5 is hydrogen.

[0680] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, VI, VIa or VIb, wherein t is 0.

[0681] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, VI, VIa or VIb, wherein t is 1, 2, or 3.

[0682] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, VI, VIa or VIb, wherein t is 1

[0683] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, VI, VIa or VIb, wherein t is 2.

[0684] While all enantiomers and mixtures thereof are useful as PKM2
modulators, in one aspect, single enantiomers are preferred. Furthermore,
while all of the compounds of the invention are useful as PKM2
modulators, certain classes are as described above. It will be understood
that the above classes may be combined to form additional classes, as for
example the combination of certain selections for two or more
substituents. Some illustrative combinations are below for Formula V, Va,
Vb, VI, VIa, and VIb.

[0685] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl or
heteroaryl; Rb is fluorine, CF3, NHC(O)CH3, NH2 or
two Rb on adjacent carbon atoms form a heterocycloalkyl ring; t is
0, 1, or 2; R3a, R3d, and R3c are each hydrogen and one of
R3b or R3c is methoxy, fluorine, chlorine, methyl, or NH2
and the remaining R3b or R3c is hydrogen or R3b and
R3c form a ring selected from:

##STR00027##

[0686] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
R3a, R3d, and R3c are each hydrogen and one of R3b or
R3c is methoxy, fluorine, chlorine, methyl, or NH2 and the
remaining R3b or R3c is hydrogen or R3b and R3c form
a ring selected from:

##STR00028##

[0687] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl or
heteroaryl; Rb is fluorine, CF3, NHC(O)CH3, NH2; t is
0, 1, or 2; R3a, R3d, and R3e are each hydrogen and one of
R3b or R3c is methoxy, fluorine, chlorine, methyl, or NH2
and the remaining R3b or R3c is hydrogen or R3b and
R3c form a ring selected from:

##STR00029##

[0688] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 1, or 2; R3a, R3b, and R3c are
each hydrogen and one of R3b or R3c is methoxy, fluorine,
chlorine, methyl, or NH2 and the remaining R3b or R3c is
hydrogen or R3b and R3c form a ring selected from:

##STR00030##

[0689] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 1; R3a, R3d, and R3c are each
hydrogen and one of R3b or R3c is methoxy, fluorine, chlorine,
methyl, or NH2 and the remaining R3b or R3c is hydrogen or
R3b and R3c form a ring selected from:

##STR00031##

[0690] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 2; R3a, R3d, and R3c are each
hydrogen and one of R3b or R3c is methoxy, fluorine, chlorine,
methyl, or NH2 and the remaining R3b or R3c is hydrogen or
R3b and R3c form a ring selected from:

##STR00032##

[0691] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
R3a, R3d, and R3e are each hydrogen and one of R3b or
R3c is methoxy, fluorine, chlorine, methyl, or NH2.

[0692] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
R3a, R3d, and R3e are each hydrogen and R3b and
R3c form a ring selected from:

##STR00033##

[0693] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
R3a, R3d, and R3e are each hydrogen and one of R3b or
R3c is methoxy.

[0694] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, or NH2; t is 0, 1, or
2; R3a, R3d, and R3e are each hydrogen and one of R3b
or R3c is methoxy.

[0695] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl or
heteroaryl; Rb is fluorine, CF3, NHC(O)CH3, or NH2 or
two Rb on adjacent carbon atoms form a heterocycloalkyl ring; t is
0, 1, or 2; one of R3b or R3c is methoxy, fluorine, chlorine,
methyl, or NH2 and the remaining R3b or R3c is hydrogen or
R3b and R3c form a ring selected from:

##STR00034##

[0696] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, or NH2 or two Rb
on adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
one of R3b or R3c is methoxy, fluorine, chlorine, methyl, or
NH2 and the remaining R3b or R3c is hydrogen or R3b
and R3c form a ring selected from:

##STR00035##

[0697] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl or
heteroaryl; Rb is fluorine, CF3, NHC(O)CH3, or NH2; t
is 0, 1, or 2; one of R3b or R3c is methoxy, fluorine,
chlorine, methyl, or NH2 and the remaining R3b or R3c is
hydrogen or R3b and R3c form a ring selected from:

##STR00036##

[0698] In one aspect, embodiments of the invention include a compound of
Formula V, Va, Vb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 1, or 2; one of R3b or R3c is
methoxy, fluorine, chlorine, methyl, or NH2 and the remaining
R3b or R3c is hydrogen or R3b and R3c form a ring
selected from:

##STR00037##

[0699] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 1; one of R3b or R3c is methoxy,
fluorine, chlorine, methyl, or NH2 and the remaining R3b or
R3c is hydrogen or R3b and R3c form a ring selected from:

##STR00038##

[0700] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine; t is 2; one of R3b or R3c is methoxy,
fluorine, chlorine, methyl, or NH2 and the remaining R3b or
R3c is hydrogen or R3b and R3c form a ring selected from:

##STR00039##

[0701] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, or NH2 or two Rb
on adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
one of R3b or R3c is methoxy, fluorine, chlorine, methyl, or
NH2.

[0702] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, NH2 or two Rb on
adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2; and
R3b and R3c form a ring selected from:

##STR00040##

[0703] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, or NH2 or two Rb
on adjacent carbon atoms form a heterocycloalkyl ring; t is 0, 1, or 2;
one of R3b or R3c is methoxy and the remaining R3b or
R3c is hydrogen.

[0704] In one aspect, embodiments of the invention include a compound of
Formula VI, VIa, VIb, wherein Ra is hydrogen; R2 is methyl;
Rb is fluorine, CF3, NHC(O)CH3, or NH2; t is 0, 1, or
2; and one of R3b or R3c is methoxy and the remaining R3b
or R3c is hydrogen.

[0707] Embodiments of the invention include a compound or a
pharmaceutically acceptable salt of a compound according to any one of
formulae of the invention. Embodiments of the invention include a
pharmaceutically acceptable salt of a compound according to any one of
formulae of the invention. Embodiments of the invention include a solvate
of a compound according to any one of formulae of the invention.
Embodiments of the invention include a hydrate of a compound according to
any one of the formulae of the invention. Embodiments of the invention
include an acid addition salt (e.g., a pharmaceutically acceptable salt)
of a compound according to any one of the formulae of the invention. For
example, the salt is a hydrochloride salt.

[0708] Embodiments of the invention include a compound of any one of
formulae I, II, III, IV, V, or VI or a pharmaceutically acceptable salt
thereof, wherein the compound is a racemate. Embodiments of the invention
include a compound of any one of formulae I, II, III, IV, V, or VI,
wherein the compound is a single enantiomer or a pharmaceutically
acceptable salt thereof. Embodiments of the invention include a compound
of any one of formulae I, II, III, IV, or VI or a pharmaceutically
acceptable salt thereof, wherein the compound is a single enantiomer that
rotates plane-polarized light in the clockwise direction (+). Embodiments
of the invention include a compound of any one of formulae I, II, III,
IV, V, or VI or a pharmaceutically acceptable salt thereof, wherein the
compound is a single enantiomer that rotates plane-polarized light in the
counterclockwise direction (-). Embodiments of the invention include a
compound of any one of formulae I, II, III, IV, V, or VI or a
pharmaceutically acceptable salt thereof, wherein the stereogenic center
attached to R5 is in the R-configuration. Embodiments of the
invention include a compound of any one of formulae I, II, III, IV, V, or
VI or a pharmaceutically acceptable salt thereof, wherein the stereogenic
center attached to R5 is in the S-configuration.

[0709] Embodiments of the invention also include a composition comprising
a compound according to any one of the formulae of the invention and at
least one pharmaceutically acceptable excipient. When the compound
according to any one of the formulae of the invention has more than one
stereoisomeric form, the pharmaceutical composition may be prepared with
a pure or an essentially pure enantiomeric form of the compound, having
an enantiopurity of at least 90% enantiomeric excess (EE), preferably at
least 95% EE, more preferably at least 98% EE, and most preferably at
least 99% EE. Alternatively, the pharmaceutical composition may be
prepared as mixture of enantiomeric forms of the compounds (e.g., as a
racemic mixture or as a mixture with a ratio of 60:40, 70:30, 80:20 or
90:10 between the enantiomeric forms).

[0710] In one aspect, compounds of the invention include any of the
compounds listed in Tables 1A and 1B or a stereoisomer, salt, solvate,
hydrate, or prodrug thereof, wherein the compound activates PKM2 by at
least about 10%, by at least about 20%, by at least about 25%, by at
least about 30%, by at least about 40%, by at least about 50%, by at
least about 60%, by at least about 70%, by at least about 75%, by at
least about 80%, by at least about 90%, or by about 95% or more.

[0711] In one aspect, embodiments of the invention include the foregoing
compounds that activate PKM2 by at least about 10%, by at least about
20%, by at least about 25%, by at least about 30%, by at least about 40%,
by at least about 50%, by at least about 60%, by at least about 70%, by
at least about 75%, by at least about 80%, by at least about 90%, or by
about 95% or more.

[0712] In one aspect, compounds of the invention are prepared using
methods known in the art. For example, compounds of the invention can be
prepared based on the procedures of Patel, P. et al. (1996) IL FARMACO
51(1), 59-63 and Jamode, V. S. et al. (2003) Indian J. Heterocyclic Chem.
12, 323-326. As shown in the scheme below, compounds of the invention can
be prepared as follows. In the first step, a substituted acetophenone (1)
can be condensed with an arylcarbonyl moiety (2) under acidic or basic
conditions to afford α, β-unsaturated ketone (3). In the next
step, the unsaturated ketone (3) can be treated with hydrazine and
substituted carboxylic acid or anhydride (4) concurrently or
sequentially, to yield the desired 2-pyrazoline product (5). The
transformation from (3) to (5) can be performed as one step or as two
separate steps.

##STR00334##

[0713] In one aspect, embodiments of the invention are drawn to methods of
activating PKM2 by contacting PKM2 with a compound of the invention,
e.g., a compound according to any one of formulae of the invention, or a
salt, solvate, hydrate, or prodrug thereof. In some embodiments, PKM2 is
activated by at least about 10%, by at least about 20%, by at least about
25%, by at least about 30%, by at least about 40%, by at least about 50%,
by at least about 60%, by at least about 70%, by at least about 75%, by
at least about 80%, by at least about 90%, or by about 95% or more. In
some embodiments, the PKM2 activated is in a cell, e.g., a human cell.

[0714] Embodiments of the invention include methods of preventing or
treating a cell proliferation-related disorder, a cancer, an inflammatory
disorder, a metabolic disorder or an autoimmune disorder by administering
to a subject in need thereof a pharmaceutical composition that includes a
compound according to embodiments of the invention, e.g., a compound
according to any one of the formulae of the invention, or a salt,
solvate, hydrate, or prodrug thereof, and at least one pharmaceutically
acceptable excipient to a subject in need thereof.

[0715] When the pharmaceutical composition includes a compound of the
invention that has more than one stereoisomeric form, the pharmaceutical
composition may be prepared with a pure or an essentially pure
enantiomeric form of the compound, with an enantiopurity of at least 90%
enantiomeric excess (EE), preferably at least 95% EE, more preferably at
least 98% EE, and most preferably at least 99% EE. Alternatively, the
pharmaceutical composition may be prepared as mixture of enantiomeric
forms of the compounds (e.g., as a racemic mixture or as a mixture with a
ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).
The invention also includes use of a compound of the invention in the
manufacture of a medicament to prevent or treat a cell
proliferation-related disorder, a cancer, an inflammatory disorder,
metabolic disorder, or an autoimmune disorder. When the medicament
includes a compound of the invention that has more than one
stereoisomeric form, the medicament may be prepared with a pure or an an
essentially pure enantiomeric form of the compound, with an enantiopurity
of at least 90% enantiomeric excess (EE), preferably at least 95% EE,
more preferably at least 98% EE, and most preferably at least 99% EE.
Alternatively, the medicament may be prepared as mixture of enantiomeric
forms of the compounds (e.g., as a racemic mixture or as a mixture with a
ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).

[0716] The invention relates to a method of treating or preventing a
disease or disorder that is modulated by PKM2 activation, by
administering a pharmaceutical composition that includes a compound of
the invention and at least one pharmaceutically acceptable excipient.
When the pharmaceutical composition includes a compound of the invention
that has more than one stereoisomeric form, the pharmaceutical
composition may be prepared with a pure or an essentially pure
enantiomeric form of the compound, with an enantiopurity of at least 90%
enantiomeric excess (EE), preferably at least 95% EE, more preferably at
least 98% EE, and most preferably at least 99% EE. Alternatively, the
pharmaceutical composition may be prepared as mixture of enantiomeric
forms of the compounds (e.g., as a racemic mixture or as a mixture with a
ratio of 60:40, 70:30, 80:20 or 90:10 between the enantiomeric forms).
For example, the disease or disorder that is modulated by PKM2 activation
is cancer, pre-cancer or a hyperproliferative disorder.

[0717] One aspect of the invention includes methods of regulating immune
system activity in a subject comprising administering a compound of the
invention. Embodiments of the invention also include use of a compound of
the invention in the manufacture of a medicament to regulate immune
system activity. Examples of diseases that may be treated or prevented
according to the foregoing methods include, but are not limited to,
allergies, asthma, autoimmune diseases such as transplant rejection
(e.g., kidney, heart, lung, liver, pancreas, skin, host versus graft
reaction (HVGR), etc.), rheumatoid arthritis, and amyotrophic lateral
sclerosis, multiple sclerosis, psoriasis and Sjogren' syndrome, Type II
inflammatory disease such as vascular inflammation (including vasculitis,
ateritis, atherosclerosis and coronary artery disease), diseases of the
central nervous system such as stroke, pulmonary diseases such as
bronchitis obliterous and primary and primary pulmonary hypertension,
delayed or cell-mediated, Type IV hypersensitivity and solid and
hematologic malignancies such as leukemias and lymphomas.

[0718] In one aspect, a compound of the invention may be used as a
pharmaceutical agent. The compounds may be used without limitation, for
example, as anti-cancer, anti-proliferative, anti-inflammatory and/or
immunosuppressive agents, for treating humans and/or animals, such as for
treating humans and/or other mammals.

[0719] In some embodiments, the administration of the compound is carried
out orally, parentally, subcutaneously, intravenously, intramuscularly,
intraperitoneally, by intranasal instillation, by intracavitary or
intravesical instillation, topically, intraarterially, intralesionally,
by metering pump, or by application to mucous membranes. In some
embodiments, the compound is administered with a pharmaceutically
acceptable carrier.

[0720] In certain embodiments, the cell proliferation disorder includes
any type of cancer including solid tumors and non-solid tumors. In
specific embodiments the solid tumors are selected from tumors in the CNS
(central nervous system), liver cancer, colorectal carcinoma, breast
cancer, gastric cancer, pancreatic cancer, bladder carcinoma, cervical
carcinoma, head and neck tumors, vulvar cancer and dermatological
neoplasms including melanoma, squamous cell carcinoma and basal cell
carcinomas. In other embodiments, non-solid tumors include
lymphoproliferative disorders including leukemias and lymphomas. In other
embodiments, the disorder is metastatic disease.

[0721] The compounds of the invention also may be used in the treatment of
a cancer or cell proliferation disorder in a combination therapy with one
or more of anti-cancer treatments such as surgery, radiation therapy,
immunotherapy and/or one or more anti-cancer agents selected from the
group consisting of anti-proliferative agents, other agents that modulate
the metabolism of cancer cells, cytotoxic agents, cytostatic agents, and
chemotherapeutic agents and salts and derivatives thereof. According to
certain embodiments, the compounds of the invention may be used in the
treatment of a cancer or cell proliferation disorder in combination
therapy with any one of the drugs selected from a group consisting of an
alkaloid, an alkylating agent, an antitumor antibiotic, an
antimetabolite, a Bcr-Abl tyrosine kinase inhibitor, a nucleoside
analogue, a multidrug resistance reversing agent, a DNA binding agent,
microtubule binding drug, a toxin and a DNA antagonist. Those of skill in
the art will recognize the chemotherapeutic agents classified into one or
more particular classes of chemotherapeutic agents described above.

[0722] When used in combination with additional anti-proliferation agents,
the compounds of the invention may enhance (e.g., synergize) the activity
of these agents. Further, such synergism would permit the compounds of
the invention, additional anti-proliferation agents, or both to be
administered at lower dosages, and/or may significantly enhance the
anti-proliferation properties of the compounds at any given dose.

DEFINITIONS

[0723] For convenience, certain terms used in the specification, examples
and appended claims are collected here.

[0724] A compound "activates PKM2" if the compound stimulates the
enzymatic activity by PKM2 of reaction 1 by at least 10% relative to the
activity of PKM2 under the same conditions but lacking only the presence
of the compound.

Phosphoenolpyruvate+ADP→Pyruvate+ATP (1)

The activity of PKM2 may be measured by any reproducible means. The
activity of PKM2 may be measured in vitro or in vivo.

[0725] For the avoidance of doubt, the term "a compound of the invention"
or "compounds of the invention" refers to any compound or compounds
disclosed herein e.g., a compound of the invention includes a compound of
formulae I, Ia, Ib, II, IIa, IIb, III, IIIc, IIIb, IV, IVa, IVb, V, Va,
Vb, VIa, and VIb and/or a compound in Tables 1, 1A and/or 1B. In some
aspects, a compound of the invention does not include a compound in
Tables 1A and 1B. Whenever the term is used in the context of the
invention it is to be understood that the reference is being made to both
the free base and the corresponding salts, solvates, and prodrugs
provided that such is possible and/or appropriate under the
circumstances.

[0726] The term "formula of the invention" or "formulae of the invention"
refers any one or more of formulae I, Ia, Ib, II, IIa, IIb, III, IIIa,
IIIb, IV, IVa, IVb, V, Va, Vb, VIa, and VIb.

[0727] "Treating", includes any effect, e.g., lessening, reducing,
modulating, or eliminating, that results in the improvement of the
condition, disease, disorder, etc. "Treating" or "treatment" of a disease
state includes: (1) inhibiting the disease state, i.e., arresting the
development of the disease state or its clinical symptoms or (2)
relieving the disease state, i.e., causing temporary or permanent
regression of the disease state or its clinical symptoms.

[0728] "Preventing" means causing the clinical symptoms of the disease
state not to develop, i.e., inhibiting the onset of disease, in a subject
that may be exposed to or predisposed to the disease state, but does not
yet experience or display symptoms of the disease state.

[0730] In some embodiments, the cell proliferation disorder is cancer. As
used herein, the term "cancer" includes solid tumors, such as lung,
breast, colon, ovarian, brain, liver, pancreas, prostate, malignant
melanoma, non-melanoma skin cancers, as well as hematologic tumors and/or
malignancies, such as childhood leukemia and lymphomas, multiple myeloma,
Hodgkin's disease, lymphomas of lymphocytic and cutaneous origin, acute
and chronic leukemia such as acute lymphoblastic, acute myelocytic or
chronic myelocytic leukemia, plasma cell neoplasm, lymphoid neoplasm and
cancers associated with AIDS.

[0731] An "effective amount" of a compound is the quantity which, when
administered to a subject having a disease or disorder, results in
regression of the disease or disorder in the subject. Thus, for example,
for a cell proliferation disorder an effective amount of a compound of
the disclosed invention is the quantity which, when administered to a
subject having a cell proliferation disorder, results in regression of
cell growth in the subject. The amount of the compound to be administered
to a subject will depend on the particular disorder, the mode of
administration, co-administered compounds, if any, and the
characteristics of the subject, such as general health, other diseases,
age, sex, genotype, body weight and tolerance to drugs. The skilled
artisan will be able to determine appropriate dosages depending on these
and other factors.

[0732] "A therapeutically effective amount" means the amount of a compound
that, when administered to a mammal, e.g., a human, for treating a
disease, is sufficient to effect such treatment for the disease. The
"therapeutically effective amount" will vary depending on the compound,
the disease and its severity and the age, weight, etc., of the mammal to
be treated.

[0733] A therapeutically effective amount of one or more of the compounds
can be formulated with a pharmaceutically acceptable carrier for
administration to a human or an animal. Accordingly, the compounds or the
formulations can be administered, for example, via oral, parenteral, or
topical routes, to provide an effective amount of the compound. In
alternative embodiments, the compounds prepared in accordance with the
invention can be used to coat or impregnate a medical device, e.g., a
stent.

[0734] The term "prophylactically effective amount" means an effective
amount of a compound or compounds, of the invention that is administered
to prevent or reduce the risk of a disease state.

[0735] "Pharmacological effect" as used herein encompasses effects
produced in the subject that achieve the intended purpose of a therapy.

[0736] With respect to the compounds useful in the invention, the
following terms can be applicable:

[0737] The term "substituted," as used herein, means that any one or more
hydrogens on the designated atom is replaced with a selection from the
indicated group, provided that the designated atom's normal valency is
not exceeded, and that the substitution results in a stable compound.
When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom
are replaced. Keto substituents are not present on aromatic moieties.
Ring double bonds, as used herein, are double bonds that are formed
between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

[0738] The invention is intended to include all isotopes of atoms
occurring in the present compounds. Isotopes include those atoms having
the same atomic number but different mass numbers. By way of general
example and without limitation, isotopes of hydrogen include tritium and
deuterium, and isotopes of carbon include C-13 and C-14.

[0739] The compounds described herein may have asymmetric centers.
Compounds of the invention containing an asymmetrically substituted atom
may be isolated in optically active or racemic forms. It is well known in
the art how to prepare optically active forms, such as by resolution of
racemic forms or by synthesis from optically active starting materials.
Many geometric isomers of olefins, C═N double bonds, and the like can
also be present in the compounds described herein, and all such stable
isomers are contemplated in the invention. Cis and trans geometric
isomers may be isolated as a mixture of isomers or as separated isomeric
forms. All chiral, diastereomeric, racemic, and geometric isomeric forms
of a structure are intended, unless the specific stereochemistry or
isomeric form is specifically indicated. All tautomers of shown or
described compounds are also considered to be part of the invention.

[0740] When any variable (e.g., Rb) occurs more than one time in any
constituent or formula for a compound, its definition at each occurrence
is independent of its definition at every other occurrence. Thus, for
example, if a group is shown to be substituted with 0-2 Rb moieties,
then the group may optionally be substituted with up to two Rb
moieties and Rb at each occurrence is selected independently from
the definition of Rb. Also, combinations of substituents and/or
variables are permissible, but only if such combinations result in stable
compounds.

[0741] When an atom or chemical moiety is followed by a subscripted
numeric range (e.g., C1-6), the invention is meant to encompass each
number within the range as well as all intermediate ranges. For example,
"C1-6 alkyl" is meant to include alkyl groups with 1, 2, 3, 4, 5, 6,
1-6, 1-5, 1-4, 1-3, 1-2, 2-6, 2-5, 2-4, 2-3, 3-6, 3-5, 3-4, 4-6, 4-5, and
5-6 carbons.

[0742] As used herein, "alkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, C1-6 alkyl is
intended to include C1, C2, C3, C4, C5, and
C6 alkyl groups. Examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl,
s-pentyl, and n-hexyl. In certain embodiments, a straight chain or
branched chain alkyl has six or fewer carbon atoms in its backbone (e.g.,
C1-C6 for straight chain, C3-C6 for branched chain),
and in another embodiment, a straight chain or branched chain alkyl has
four or fewer carbon atoms. Likewise, cycloalkyls have from three to
eight carbon atoms in their ring structure, and in other embodiments,
cycloalkyls have five or six carbons in the ring structure.

[0743] The term "heteroalkyl" refers to an alkyl group in which one or
more skeletal atoms of the alkyl are selected from an atom other than
carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations
thereof.

[0744] Unless the number of carbons is otherwise specified, "lower alkyl"
includes an alkyl group, as defined above, but having from one to ten, or
in other embodiments from one to six, carbon atoms in its backbone
structure. "Lower alkenyl" and "lower alkynyl" have chain lengths of, for
example, 2-6 carbon atoms.

[0746] "Alkenyl" includes unsaturated aliphatic groups analogous in length
and possible substitution to the alkyls described above, but that contain
at least one double bond. For example, the term "alkenyl" includes
straight-chain alkenyl groups (e.g., ethenyl, propenyl, butenyl,
pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl), branched-chain
alkenyl groups, cycloalkenyl (e.g., alicyclic) groups (e.g.,
cyclopropenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl),
alkyl or alkenyl substituted cycloalkenyl groups, and cycloalkyl or
cycloalkenyl substituted alkenyl groups. In certain embodiments, a
straight chain or branched chain alkenyl group has six or fewer carbon
atoms in its backbone (e.g., C2-C6 for straight chain,
C3-C6 for branched chain). Likewise, cycloalkenyl groups may
have from three to eight carbon atoms in their ring structure, and in
some embodiments, cycloalkenyl groups have five or six carbons in the
ring structure. The term "C2-C6" includes alkenyl groups
containing two to six carbon atoms. The term "C3-C6" includes
alkenyl groups containing three to six carbon atoms.

[0748] "Alkynyl" includes unsaturated aliphatic groups analogous in length
and possible substitution to the alkyls described above, but which
contain at least one triple bond. For example, "alkynyl" includes
straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl,
pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl), branched-chain
alkynyl groups, and cycloalkyl or cycloalkenyl substituted alkynyl
groups. In certain embodiments, a straight chain or branched chain
alkynyl group has six or fewer carbon atoms in its backbone (e.g.,
C2-C6 for straight chain, C3-C6 for branched chain).
The term "C2-C6" includes alkynyl groups containing two to six
carbon atoms. The term "C3-C6" includes alkynyl groups
containing three to six carbon atoms.

[0754] As used herein, "carbocycle" or "carbocyclic ring" is intended to
mean any stable monocyclic, bicyclic, or tricyclic ring having the
specified number of carbons, any of which may be saturated, unsaturated,
or aromatic. For example a C3-14 carbocycle is intended to mean a
mono-, bi-, or tricyclic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
or 14 carbon atoms. Examples of carbocycles include, but are not limited
to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,
cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl,
indanyl, adamantyl, and tetrahydronaphthyl. Bridged rings are also
included in the definition of carbocycle, including, for example,
[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, and
[2.2.2]bicyclooctane. A bridged ring occurs when one or more carbon atoms
link two non-adjacent carbon atoms. In some embodiments, bridge rings are
one or two carbon atoms. It is noted that a bridge always converts a
monocyclic ring into a tricyclic ring. When a ring is bridged, the
substituents recited for the ring may also be present on the bridge.
Fused (e.g., naphthyl and tetrahydronaphthyl) and spiro rings are also
included.

[0755] As used herein, the term "heterocycle" or "heterocyclic" is
intended to mean any stable monocyclic, bicyclic, or tricyclic ring which
is saturated, unsaturated, or aromatic and comprises carbon atoms and one
or more ring heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6
heteroatoms, independently selected from the group consisting of
nitrogen, oxygen, and sulfur. A bicyclic or tricyclic heterocycle may
have one or more heteroatoms located in one ring, or the heteroatoms may
be located in more than one ring. The nitrogen and sulfur heteroatoms may
optionally be oxidized (i.e., N→O and S(O)p, where p=1 or 2).
When a nitrogen atom is included in the ring it is either N or NH,
depending on whether or not it is attached to a double bond in the ring
(i.e., a hydrogen is present if needed to maintain the tri-valency of the
nitrogen atom). The nitrogen atom may be substituted or unsubstituted
(i.e., N or NR wherein R is H or another substituent, as defined). The
heterocyclic ring may be attached to its pendant group at any heteroatom
or carbon atom that results in a stable structure. The heterocyclic rings
described herein may be substituted on carbon or on a nitrogen atom if
the resulting compound is stable. A nitrogen in the heterocycle may
optionally be quaternized. In some embodiments, when the total number of
S and O atoms in the heterocycle exceeds 1, then these heteroatoms are
not adjacent to one another. Bridged rings are also included in the
definition of heterocycle. A bridged ring occurs when one or more atoms
(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
Bridges include, but are not limited to, one carbon atom, two carbon
atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen
group. It is noted that a bridge always converts a monocyclic ring into a
tricyclic ring. When a ring is bridged, the substituents recited for the
ring may also be present on the bridge. Spiro and fused rings are also
included.

[0756] As used herein, the term "aromatic heterocycle" or "heteroaryl" is
intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic
aromatic heterocyclic ring or 7, 8, 9, 10, 11, or 12-membered bicyclic
aromatic heterocyclic ring which consists of carbon atoms and one or more
heteroatoms, e.g., 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms,
independently selected from the group consisting of nitrogen, oxygen, and
sulfur. In the case of bicyclic heterocyclic aromatic rings, only one of
the two rings needs to be aromatic (e.g., 2,3-dihydroindole), though both
may be (e.g., quinoline). The second ring can also be fused or bridged as
defined above for heterocycles. The nitrogen atom may be substituted or
unsubstituted (i.e., N or NR wherein R is H or another substituent, as
defined). The nitrogen and sulfur heteroatoms may optionally be oxidized
(i.e., N→O and S(O)p, where p=1 or 2). It is to be noted that
total number of S and O atoms in the aromatic heterocycle is not more
than 1.

[0759] "Acylamino" includes moieties wherein an acyl moiety is bonded to
an amino group. For example, the term includes alkylcarbonylamino,
arylcarbonylamino, carbamoyl and ureido groups.

[0760] "Aroyl" includes compounds and moieties with an aryl or
heteroaromatic moiety bound to a carbonyl group. Examples of aroyl groups
include phenylcarboxy, naphthyl carboxy, etc.

[0761] "Alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include
alkyl groups, as described above, which further include oxygen, nitrogen
or sulfur atoms replacing one or more hydrocarbon backbone carbon atoms,
e.g., oxygen, nitrogen or sulfur atoms.

[0763] The term "thiocarbonyl" or "thiocarboxy" includes compounds and
moieties which contain a carbon connected with a double bond to a sulfur
atom.

[0764] The term "ether" or "alkoxy" includes compounds or moieties which
contain an oxygen bonded to two different carbon atoms or heteroatoms.
For example, the term includes "alkoxyalkyl" which refers to an alkyl,
alkenyl, or alkynyl group covalently bonded to an oxygen atom which is
covalently bonded to another alkyl group.

[0765] The term "ester" includes compounds and moieties which contain a
carbon or a heteroatom bound to an oxygen atom which is bonded to the
carbon of a carbonyl group. The term "ester" includes alkoxycarboxy
groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
butoxycarbonyl, pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl
groups are as defined above.

[0766] The term "thioether" includes compounds and moieties which contain
a sulfur atom bonded to two different carbon or heteroatoms. Examples of
thioethers include, but are not limited to alkthioalkyls,
alkthioalkenyls, and alkthioalkynyls. The term "alkthioalkyls" include
compounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfur
atom which is bonded to an alkyl group. Similarly, the term
"alkthioalkenyls" and alkthioalkynyls" refer to compounds or moieties
wherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atom
which is covalently bonded to an alkynyl group.

[0767] The term "hydroxy" or "hydroxyl" includes groups with an --OH or
--O.sup.-.

[0768] "Polycyclyl" or "polycyclic radical" refers to two or more cyclic
rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or
heterocyclyls) in which two or more carbons are common to two adjoining
rings. Rings that are joined through non-adjacent atoms are termed
"bridged" rings. Each of the rings of the polycycle can be substituted
with such substituents as described above, as for example, halogen,
hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,
aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,
alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl,
alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl,
aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,
phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino,
diarylamino, and alkylarylamino), acylamino (including
alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,
imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,
alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,
cyano, azido, heterocyclyl, alkyl, alkylaryl, or an aromatic or
heteroaromatic moiety.

[0769] An "anionic group," as used herein, refers to a group that is
negatively charged at physiological pH. Anionic groups include
carboxylate, sulfate, sulfonate, sulfinate, sulfamate, tetrazolyl,
phosphate, phosphonate, phosphinate, or phosphorothioate or functional
equivalents thereof "Functional equivalents" of anionic groups are
intended to include bioisosteres, e.g., bioisosteres of a carboxylate
group. Bioisosteres encompass both classical bioisosteric equivalents and
non-classical bioisosteric equivalents. Classical and non-classical
bioisosteres are known in the art (see, e.g., Silverman, R. B. The
Organic Chemistry of Drug Design and Drug Action, Academic Press, Inc.:
San Diego, Calif., 1992, pp. 19-23). In some embodiments, an anionic
group is a carboxylate.

[0770] In the specification, the structural formula of the compound
represents a certain isomer for convenience in some cases, but the
invention includes all isomers such as geometrical isomer, optical isomer
based on an asymmetrical carbon, stereoisomer, tautomer and the like
which occur structurally and an isomer mixture and is not limited to the
description of the formula for convenience, and may be any one isomer or
a mixture. Therefore, an asymmetrical carbon atom may be present in the
molecule and an optically active compound and a racemic compound may be
present in the compound, but the invention is not limited to them and
includes any one. In addition, a crystal polymorphism may be present but
is not limiting, but any crystal form may be single or a crystal form
mixture, or an anhydride or hydrate. Further, so-called metabolite which
is produced by degradation of the compound in vivo is included in the
scope of the invention.

[0771] "Isomerism" means compounds that have identical molecular formulae
but that differ in the nature or the sequence of bonding of their atoms
or in the arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable mirror
images are termed "enantiomers", or sometimes optical isomers. A carbon
atom bonded to four nonidentical substituents is termed a "chiral
center".

[0772] "Chiral isomer" means a compound with at least one chiral center.
It has two enantiomeric forms of opposite chirality and may exist either
as an individual enantiomer or as a mixture of enantiomers. A mixture
containing equal amounts of individual enantiomeric forms of opposite
chirality is termed a "racemic mixture". A compound that has more than
one chiral center has 2n-1 enantiomeric pairs, where n is the number
of chiral centers. Compounds with more than one chiral center may exist
as either an individual diastereomer or as a mixture of diastereomers,
termed a "diastereomeric mixture". When one chiral center is present, a
stereoisomer may be characterized by the absolute configuration (R or S)
of that chiral center. Absolute configuration refers to the arrangement
in space of the substituents attached to the chiral center. The
substituents attached to the chiral center under consideration are ranked
in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et
al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al.,
Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London),
612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964,
41, 116).

[0773] "Geometric Isomer" means the diastereomers that owe their existence
to hindered rotation about double bonds. These configurations are
differentiated in their names by the prefixes cis and trans, or Z and E,
which indicate that the groups are on the same or opposite side of the
double bond in the molecule according to the Cahn-Ingold-Prelog rules.

[0774] Further, the structures and other compounds discussed in this
application include all atropic isomers thereof. "Atropic isomers" are a
type of stereoisomer in which the atoms of two isomers are arranged
differently in space. Atropic isomers owe their existence to a restricted
rotation caused by hindrance of rotation of large groups about a central
bond. Such atropic isomers typically exist as a mixture, however as a
result of recent advances in chromatography techniques, it has been
possible to separate mixtures of two atropic isomers in select cases.

[0775] The terms "crystal polymorph" or "polymorph" or "crystal form"
means crystal structures in which a compound (or salt or solvate thereof)
can crystallize in different crystal packing arrangements, all of which
have the same elemental composition. Different crystal forms usually have
different X-ray diffraction patterns, infrared spectral, melting points,
density hardness, crystal shape, optical and electrical properties,
stability and solubility. Recrystallization solvent, rate of
crystallization, storage temperature, and other factors may cause one
crystal form to dominate. Crystal polymorphs of the compounds can be
prepared by crystallization under different conditions.

[0776] Additionally, the compounds of the invention, for example, the
salts of the compounds, can exist in either hydrated or unhydrated (the
anhydrous) form or as solvates with other solvent molecules. Nonlimiting
examples of hydrates include monohydrates, dihydrates, etc. Nonlimiting
examples of solvates include ethanol solvates, acetone solvates, etc.

[0777] "Solvate" means solvent addition forms that contain either
stoichiometric or non stoichiometric amounts of solvent. Some compounds
have a tendency to trap a fixed molar ratio of solvent molecules in the
crystalline solid state, thus forming a solvate. If the solvent is water
the solvate formed is a hydrate, when the solvent is alcohol, the solvate
formed is an alcoholate. Hydrates are formed by the combination of one or
more molecules of water with one of the substances in which the water
retains its molecular state as H2O, such combination being able to
form one or more hydrate.

[0778] "Tautomer" refers to compounds whose structures differ markedly in
arrangement of atoms, but which exist in easy and rapid equilibrium. It
is to be understood that the compounds of the invention may be depicted
as different tautomers. It should also be understood that when compounds
have tautomeric forms, all tautomeric forms are intended to be within the
scope of the invention, and the naming of the compounds does not exclude
any tautomer form.

[0779] Some compounds of the invention can exist in tautomeric forms,
which are also intended to be encompassed within the scope of the
invention.

[0780] The compounds, salts and prodrugs of the invention can exist in
several tautomeric forms, including the enol and imine form, and the keto
and enamine form and geometric isomers and mixtures thereof. All such
tautomeric forms are included within the scope of the invention.
Tautomers exist as mixtures of a tautomeric set in solution. In solid
form, usually one tautomer predominates. Even though one tautomer may be
described, the invention includes all tautomers of the compounds.

[0781] A tautomer is one of two or more structural isomers that exist in
equilibrium and are readily converted from one isomeric form to another.
This reaction results in the formal migration of a hydrogen atom
accompanied by a switch of adjacent conjugated double bonds. In solutions
where tautomerization is possible, a chemical equilibrium of the
tautomers will be reached. The exact ratio of the tautomers depends on
several factors, including temperature, solvent, and pH. The concept of
tautomers that are interconvertable by tautomerizations is called
tautomerism.

[0782] Of the various types of tautomerism that are possible, two are
commonly observed. In keto-enol tautomerism a simultaneous shift of
electrons and a hydrogen atom occurs. Ring-chain tautomerism, is
exhibited by glucose. It arises as a result of the aldehyde group (--CHO)
in a sugar chain molecule reacting with one of the hydroxy groups (--OH)
in the same molecule to give it a cyclic (ring-shaped) form.

[0783] Tautomerizations are catalyzed by: Base: 1. deprotonation; 2.
formation of a delocalized anion (e.g. an enolate); 3. protonation at a
different position of the anion; Acid: 1. protonation; 2. formation of a
delocalized cation; 3. deprotonation at a different position adjacent to
the cation.

[0785] It will be noted that the structure of some of the compounds of the
invention include asymmetric carbon atoms. It is to be understood
accordingly that the isomers arising from such asymmetry (e.g., all
enantiomers and diastereomers) are included within the scope of the
invention, unless indicated otherwise. Such isomers can be obtained in
substantially pure form by classical separation techniques and by
stereochemically controlled synthesis. Furthermore, the structures and
other compounds and moieties discussed in this application also include
all tautomers thereof. Alkenes can include either the E- or Z-geometry,
where appropriate. The compounds of this invention may exist in
stereoisomeric form, therefore can be produced as individual
stereoisomers or as mixtures.

[0786] As used herein, the term "analog" refers to a compound that is
structurally similar to another but differs slightly in composition (as
in the replacement of one atom by an atom of a different element or in
the presence of a particular functional group, or the replacement of one
functional group by another functional group). Thus, an analog is a
compound that is similar or comparable in function and appearance, but
not in structure or origin to the reference compound.

[0787] As defined herein, the term "derivative", refers to compounds that
have a common core structure, and are substituted with various groups as
described herein. For example, all of the compounds represented by
Formula I are pyrazoline derivatives, and have pyrazoline as a common
core.

[0788] A "pharmaceutical composition" is a formulation containing the
compounds in a form suitable for administration to a subject. In some
embodiments, the pharmaceutical composition is in bulk or in unit dosage
form. The unit dosage form is any of a variety of forms, including, for
example, a capsule, an IV bag, a tablet, a single pump on an aerosol
inhaler, or a vial. The quantity of active ingredient (e.g., a
formulation of the disclosed compound or salt, hydrate, solvate, or
isomer thereof) in a unit dose of composition is an effective amount and
is varied according to the particular treatment involved. One skilled in
the art will appreciate that it is sometimes necessary to make routine
variations to the dosage depending on the age and condition of the
patient. The dosage will also depend on the route of administration. A
variety of routes are contemplated, including oral, pulmonary, rectal,
parenteral, transdermal, subcutaneous, intravenous, intramuscular,
intraperitoneal, inhalational, buccal, sublingual, intrapleural,
intrathecal, intranasal, and the like. Dosage forms for the topical or
transdermal administration of a compound of this invention include
powders, sprays, ointments, pastes, creams, lotions, gels, solutions,
patches and inhalants. In some embodiments, the active compound is mixed
under sterile conditions with a pharmaceutically acceptable carrier, and
with any preservatives, buffers, or propellants that are required.

[0789] The term "immediate release" is defined as a release of compound
from a dosage form in a relatively brief period of time, generally up to
about 60 minutes. The term "modified release" is defined to include
delayed release, extended release, and pulsed release. The term "pulsed
release" is defined as a series of releases of drug from a dosage form.
The term "sustained release" or "extended release" is defined as
continuous release of a compound from a dosage form over a prolonged
period.

[0791] As used herein, the phrase "pharmaceutically acceptable" refers to
those compounds, materials, compositions, carriers, and/or dosage forms
which are, within the scope of sound medical judgment, suitable for use
in contact with the tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication, commensurate with a reasonable benefit/risk ratio.

[0792] "Pharmaceutically acceptable excipient" means an excipient that is
useful in preparing a pharmaceutical composition that is generally safe,
non-toxic and neither biologically nor otherwise undesirable, and
includes excipient that is acceptable for veterinary use as well as human
pharmaceutical use. A "pharmaceutically acceptable excipient" as used
herein includes both one and more than one such excipient.

[0793] The compounds of the invention are capable of further forming
salts. All of these forms are also contemplated within the scope of the
invention.

[0794] "Pharmaceutically acceptable salt" of a compound means a salt that
is pharmaceutically acceptable and that possesses the desired
pharmacological activity of the parent compound.

[0797] It should be understood that all references to pharmaceutically
acceptable salts include solvent addition forms (solvates) or crystal
forms (polymorphs) as defined herein, of the same salt.

[0798] The pharmaceutically acceptable salts of the invention can be
synthesized from a parent compound that contains a basic or acidic moiety
by conventional chemical methods. Generally, such salts can be prepared
by reacting the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in water or in an
organic solvent, or in a mixture of the two; non-aqueous media like
ether, ethyl acetate, ethanol, isopropanol, or acetonitrile can be used.
Lists of suitable salts are found in Remington's Pharmaceutical Sciences,
18th ed. (Mack Publishing Company, 1990). For example, salts can include,
but are not limited to, the hydrochloride and acetate salts of the
aliphatic amine-containing, hydroxyl amine-containing, and
imine-containing compounds of the invention.

[0799] Compounds of the invention can also be prepared as esters, for
example pharmaceutically acceptable esters. For example a carboxylic acid
function group in a compound can be converted to its corresponding ester,
e.g., a methyl, ethyl, or other ester. Also, an alcohol group in a
compound can be converted to its corresponding ester, e.g., an acetate,
propionate, or other ester.

[0800] Compounds of the invention can also be prepared as prodrugs, for
example pharmaceutically acceptable prodrugs. The terms "pro-drug" and
"prodrug" are used interchangeably herein and refer to any compound which
releases an active parent drug in vivo. Since prodrugs are known to
enhance numerous desirable qualities of pharmaceuticals (e.g.,
solubility, bioavailability, manufacturing, etc.) the compounds of the
invention can be delivered in prodrug form. Thus, the invention is
intended to cover prodrugs of the presently claimed compounds, methods of
delivering the same and compositions containing the same. "Prodrugs" are
intended to include any covalently bonded carriers that release an active
parent drug of the invention in vivo when such prodrug is administered to
a subject. Prodrugs may be prepared by modifying functional groups
present in the compound in such a way that the modifications are cleaved,
either in routine manipulation or in vivo, to the parent compound.
Prodrugs include compounds of the invention wherein a hydroxy, amino,
sulfhydryl, carboxy, or carbonyl group is bonded to any group that may be
cleaved in vivo to form a free hydroxyl, free amino, free sulfhydryl,
free carboxy or free carbonyl group, respectively.

[0802] "Stable compound" and "stable structure" are meant to indicate a
compound that is sufficiently robust to survive isolation to a useful
degree of purity from a reaction mixture, and formulation into an
efficacious therapeutic agent.

[0803] In the specification, the singular forms also include the plural,
unless the context clearly dictates otherwise. Unless defined otherwise,
all technical and scientific terms used herein have the same meaning as
commonly understood by one of ordinary skill in the art to which this
invention belongs. In the case of conflict, the specification will
control.

[0804] All percentages and ratios used herein, unless otherwise indicated,
are by weight.

[0805] The invention provides methods for the treatment of a cell
proliferative disorder in a subject in need thereof by administering to a
subject in need of such treatment, a therapeutically effective amount of
a compound of the invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, polymorph or solvate thereof. The cell proliferative
disorder can be cancer or a precancerous condition. The invention further
provides the use of a compound of the invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, polymorph or solvate thereof, for
the preparation of a medicament useful for the treatment of a cell
proliferative disorder.

[0806] The invention also provides methods of protecting against a cell
proliferative disorder in a subject in need thereof by administering a
therapeutically effective amount of compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, to a subject in need of such treatment. The cell
proliferative disorder can be cancer or a precancerous condition. The
invention also provides the use of compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, for the preparation of a medicament useful for the
prevention of a cell proliferative disorder.

[0807] As used herein, a "subject in need thereof" is a subject having a
cell proliferative disorder, or a subject having an increased risk of
developing a cell proliferative disorder relative to the population at
large. A subject in need thereof can have a precancerous condition.
Preferably, a subject in need thereof has cancer. A "subject" includes a
mammal. The mammal can be e.g., any mammal, e.g., a human, primate, bird,
mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or a pig.
Preferably, the mammal is a human.

[0808] As used herein, the term "cell proliferative disorder" refers to
conditions in which unregulated or abnormal growth, or both, of cells can
lead to the development of an unwanted condition or disease, which may or
may not be cancerous. Exemplary cell proliferative disorders of the
invention encompass a variety of conditions wherein cell division is
deregulated. Exemplary cell proliferative disorder include, but are not
limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous
conditions, in situ tumors, encapsulated tumors, metastatic tumors,
liquid tumors, solid tumors, immunological tumors, hematological tumors,
cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing
cells. The term "rapidly dividing cell" as used herein is defined as any
cell that divides at a rate that exceeds or is greater than what is
expected or observed among neighboring or juxtaposed cells within the
same tissue. A cell proliferative disorder includes a precancer or a
precancerous condition. A cell proliferative disorder includes cancer. In
one aspect, the methods provided herein are used to treat or alleviate a
symptom of cancer. The term "cancer" includes solid tumors, as well as,
hematologic tumors and/or malignancies. A "precancer cell" or
"precancerous cell" is a cell manifesting a cell proliferative disorder
that is a precancer or a precancerous condition. A "cancer cell" or
"cancerous cell" is a cell manifesting a cell proliferative disorder that
is a cancer. Any reproducible means of measurement may be used to
identify cancer cells or precancerous cells. Cancer cells or precancerous
cells can be identified by histological typing or grading of a tissue
sample (e.g., a biopsy sample). Cancer cells or precancerous cells can be
identified through the use of appropriate molecular markers.

[0811] A "cell proliferative disorder of the hematologic system" is a cell
proliferative disorder involving cells of the hematologic system. A cell
proliferative disorder of the hematologic system can include lymphoma,
leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign
monoclonal gammopathy, lymphomatoid granulomatosis, lymphomatoid
papulosis, polycythemia vera, chronic myelocytic leukemia, agnogenic
myeloid metaplasia, and essential thrombocythemia. A cell proliferative
disorder of the hematologic system can include hyperplasia, dysplasia,
and metaplasia of cells of the hematologic system. In one aspect,
compositions of the invention may be used to treat a cancer selected from
the group consisting of a hematologic cancer of the invention or a
hematologic cell proliferative disorder of the invention. A hematologic
cancer of the t invention can include multiple myeloma, lymphoma
(including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood
lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia
(including childhood leukemia, hairy-cell leukemia, acute lymphocytic
leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia,
chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell
leukemia), myeloid neoplasms and mast cell neoplasms.

[0812] A "cell proliferative disorder of the lung" is a cell proliferative
disorder involving cells of the lung. Cell proliferative disorders of the
lung can include all forms of cell proliferative disorders affecting lung
cells. Cell proliferative disorders of the lung can include lung cancer,
a precancer or precancerous condition of the lung, benign growths or
lesions of the lung, and malignant growths or lesions of the lung, and
metastatic lesions in tissue and organs in the body other than the lung.
Compositions of the invention may be used to treat lung cancer or cell
proliferative disorders of the lung. Lung cancer can include all forms of
cancer of the lung. Lung cancer can include malignant lung neoplasms,
carcinoma in situ, typical carcinoid tumors, and atypical carcinoid
tumors. Lung cancer can include small cell lung cancer ("SCLC"),
non-small cell lung cancer ("NSCLC"), squamous cell carcinoma,
adenocarcinoma, small cell carcinoma, large cell carcinoma, adenosquamous
cell carcinoma, and mesothelioma. Lung cancer can include "scar
carcinoma", bronchioalveolar carcinoma, giant cell carcinoma, spindle
cell carcinoma, and large cell neuroendocrine carcinoma. Lung cancer can
include lung neoplasms having histologic and ultrastructual heterogeneity
(e.g., mixed cell types).

[0813] Cell proliferative disorders of the lung can include all forms of
cell proliferative disorders affecting lung cells. Cell proliferative
disorders of the lung can include lung cancer, precancerous conditions of
the lung. Cell proliferative disorders of the lung can include
hyperplasia, metaplasia, and dysplasia of the lung. Cell proliferative
disorders of the lung can include asbestos-induced hyperplasia, squamous
metaplasia, and benign reactive mesothelial metaplasia. Cell
proliferative disorders of the lung can include replacement of columnar
epithelium with stratified squamous epithelium, and mucosal dysplasia.
Individuals exposed to inhaled injurious environmental agents such as
cigarette smoke and asbestos may be at increased risk for developing cell
proliferative disorders of the lung. Prior lung diseases that may
predispose individuals to development of cell proliferative disorders of
the lung can include chronic interstitial lung disease, necrotizing
pulmonary disease, scleroderma, rheumatoid disease, sarcoidosis,
interstitial pneumonitis, tuberculosis, repeated pneumonias, idiopathic
pulmonary fibrosis, granulomata, asbestosis, fibrosing alveolitis, and
Hodgkin's disease.

[0814] A "cell proliferative disorder of the colon" is a cell
proliferative disorder involving cells of the colon. In one aspect, the
cell proliferative disorder of the colon is colon cancer. In one aspect,
compositions of the invention may be used to treat colon cancer or cell
proliferative disorders of the colon. Colon cancer can include all forms
of cancer of the colon. Colon cancer can include sporadic and hereditary
colon cancers. Colon cancer can include malignant colon neoplasms,
carcinoma in situ, typical carcinoid tumors, and atypical carcinoid
tumors. Colon cancer can include adenocarcinoma, squamous cell carcinoma,
and adenosquamous cell carcinoma. Colon cancer can be associated with a
hereditary syndrome selected from the group consisting of hereditary
nonpolyposis colorectal cancer, familial adenomatous polyposis, Gardner's
syndrome, Peutz-Jeghers syndrome, Turcot's syndrome and juvenile
polyposis. Colon cancer can be caused by a hereditary syndrome selected
from the group consisting of hereditary nonpolyposis colorectal cancer,
familial adenomatous polyposis, Gardner's syndrome, Peutz-Jeghers
syndrome, Turcot's syndrome and juvenile polyposis.

[0815] Cell proliferative disorders of the colon can include all forms of
cell proliferative disorders affecting colon cells. Cell proliferative
disorders of the colon can include colon cancer, precancerous conditions
of the colon, adenomatous polyps of the colon and metachronous lesions of
the colon. A cell proliferative disorder of the colon can include
adenoma. Cell proliferative disorders of the colon can be characterized
by hyperplasia, metaplasia, and dysplasia of the colon. Prior colon
diseases that may predispose individuals to development of cell
proliferative disorders of the colon can include prior colon cancer.
Current disease that may predispose individuals to development of cell
proliferative disorders of the colon can include Crohn's disease and
ulcerative colitis. A cell proliferative disorder of the colon can be
associated with a mutation in a gene selected from the group consisting
of p53, ras, FAP and DCC. An individual can have an elevated risk of
developing a cell proliferative disorder of the colon due to the presence
of a mutation in a gene selected from the group consisting of p53, ras,
FAP and DCC.

[0816] A "cell proliferative disorder of the pancreas" is a cell
proliferative disorder involving cells of the pancreas. Cell
proliferative disorders of the pancreas can include all forms of cell
proliferative disorders affecting pancreatic cells. Cell proliferative
disorders of the pancreas can include pancreas cancer, a precancer or
precancerous condition of the pancreas, hyperplasia of the pancreas, and
dysaplasia of the pancreas, benign growths or lesions of the pancreas,
and malignant growths or lesions of the pancreas, and metastatic lesions
in tissue and organs in the body other than the pancreas. Pancreatic
cancer includes all forms of cancer of the pancreas. Pancreatic cancer
can include ductal adenocarcinoma, adenosquamous carcinoma, pleomorphic
giant cell carcinoma, mucinous adenocarcinoma, osteoclast-like giant cell
carcinoma, mucinous cystadenocarcinoma, acinar carcinoma, unclassified
large cell carcinoma, small cell carcinoma, pancreatoblastoma, papillary
neoplasm, mucinous cystadenoma, papillary cystic neoplasm, and serous
cystadenoma. Pancreatic cancer can also include pancreatic neoplasms
having histologic and ultrastructual heterogeneity (e.g., mixed cell
types).

[0817] A "cell proliferative disorder of the prostate" is a cell
proliferative disorder involving cells of the prostate. Cell
proliferative disorders of the prostate can include all forms of cell
proliferative disorders affecting prostate cells. Cell proliferative
disorders of the prostate can include prostate cancer, a precancer or
precancerous condition of the prostate, benign growths or lesions of the
prostate, and malignant growths or lesions of the prostate, and
metastatic lesions in tissue and organs in the body other than the
prostate. Cell proliferative disorders of the prostate can include
hyperplasia, metaplasia, and dysplasia of the prostate.

[0818] A "cell proliferative disorder of the skin" is a cell proliferative
disorder involving cells of the skin. Cell proliferative disorders of the
skin can include all forms of cell proliferative disorders affecting skin
cells. Cell proliferative disorders of the skin can include a precancer
or precancerous condition of the skin, benign growths or lesions of the
skin, melanoma, malignant melanoma and other malignant growths or lesions
of the skin, and metastatic lesions in tissue and organs in the body
other than the skin. Cell proliferative disorders of the skin can include
hyperplasia, metaplasia, and dysplasia of the skin.

[0819] A "cell proliferative disorder of the ovary" is a cell
proliferative disorder involving cells of the ovary. Cell proliferative
disorders of the ovary can include all forms of cell proliferative
disorders affecting cells of the ovary. Cell proliferative disorders of
the ovary can include a precancer or precancerous condition of the ovary,
benign growths or lesions of the ovary, ovarian cancer, malignant growths
or lesions of the ovary, and metastatic lesions in tissue and organs in
the body other than the ovary. Cell proliferative disorders of the skin
can include hyperplasia, metaplasia, and dysplasia of cells of the ovary.

[0820] A "cell proliferative disorder of the breast" is a cell
proliferative disorder involving cells of the breast. Cell proliferative
disorders of the breast can include all forms of cell proliferative
disorders affecting breast cells. Cell proliferative disorders of the
breast can include breast cancer, a precancer or precancerous condition
of the breast, benign growths or lesions of the breast, and malignant
growths or lesions of the breast, and metastatic lesions in tissue and
organs in the body other than the breast. Cell proliferative disorders of
the breast can include hyperplasia, metaplasia, and dysplasia of the
breast.

[0821] A cell proliferative disorder of the breast can be a precancerous
condition of the breast. Compositions of the invention may be used to
treat a precancerous condition of the breast. A precancerous condition of
the breast can include atypical hyperplasia of the breast, ductal
carcinoma in situ (DCIS), intraductal carcinoma, lobular carcinoma in
situ (LCIS), lobular neoplasia, and stage 0 or grade 0 growth or lesion
of the breast (e.g., stage 0 or grade 0 breast cancer, or carcinoma in
situ). A precancerous condition of the breast can be staged according to
the TNM classification scheme as accepted by the American Joint Committee
on Cancer (AJCC), where the primary tumor (T) has been assigned a stage
of T0 or Tis; and where the regional lymph nodes (N) have been assigned a
stage of N0; and where distant metastasis (M) has been assigned a stage
of M0.

[0822] The cell proliferative disorder of the breast can be breast cancer.
Breast cancer includes all forms of cancer of the breast. Breast cancer
can include primary epithelial breast cancers. Breast cancer can include
cancers in which the breast is involved by other tumors such as lymphoma,
sarcoma or melanoma. Breast cancer can include carcinoma of the breast,
ductal carcinoma of the breast, lobular carcinoma of the breast,
undifferentiated carcinoma of the breast, cystosarcoma phyllodes of the
breast, angiosarcoma of the breast, and primary lymphoma of the breast.
Breast cancer can include Stage I, II, IIIA, IIIB, IIIC and IV breast
cancer. Ductal carcinoma of the breast can include invasive carcinoma,
invasive carcinoma in situ with predominant intraductal component,
inflammatory breast cancer, and a ductal carcinoma of the breast with a
histologic type selected from the group consisting of comedo, mucinous
(colloid), medullary, medullary with lymphcytic infiltrate, papillary,
scirrhous, and tubular. Lobular carcinoma of the breast can include
invasive lobular carcinoma with predominant in situ component, invasive
lobular carcinoma, and infiltrating lobular carcinoma. Breast cancer can
include Paget's disease, Paget's disease with intraductal carcinoma, and
Paget's disease with invasive ductal carcinoma. Breast cancer can include
breast neoplasms having histologic and ultrastructual heterogeneity
(e.g., mixed cell types).

[0823] A breast cancer that is to be treated can include familial breast
cancer. A breast cancer that is to be treated can include sporadic breast
cancer. A breast cancer that is to be treated can arise in a male
subject. A breast cancer that is to be treated can arise in a female
subject. A breast cancer that is to be treated can arise in a
premenopausal female subject or a postmenopausal female subject. A breast
cancer that is to be treated can arise in a subject equal to or older
than 30 years old, or a subject younger than 30 years old. A breast
cancer that is to be treated has arisen in a subject equal to or older
than 50 years old, or a subject younger than 50 years old. A breast
cancer that is to be treated can arise in a subject equal to or older
than 70 years old, or a subject younger than 70 years old.

[0824] A breast cancer that is to be treated can be typed to identify a
familial or spontaneous mutation in BRCA1, BRCA2, or p53. A breast cancer
that is to be treated can be typed as having a HER2/neu gene
amplification, as overexpressing HER2/neu, or as having a low,
intermediate or high level of HER2/neu expression. A breast cancer
that is to be treated can be typed as HER2-negative or
HER2-positive. HER2-typing of a breast cancer may be performed
by any reproducible means. A breast cancer that is to be treated can be
typed for a marker selected from the group consisting of estrogen
receptor (ER), progesterone receptor (PR), human epidermal growth factor
receptor-2, Ki-67, CA15-3, CA 27-29, and c-Met. A breast cancer that is
to be treated can be typed as ER-unknown, ER-rich or ER-poor. A breast
cancer that is to be treated can be typed as ER-negative or ER-positive.
ER-typing of a breast cancer may be performed by any reproducible means.
ER-typing of a breast cancer may be performed as set forth in Onkologie
27: 175-179 (2004). A breast cancer that is to be treated can be typed as
PR-unknown, PR-rich or PR-poor. A breast cancer that is to be treated can
be typed as PR-negative or PR-positive. PR-typing of a breast cancer may
be performed by any reproducible means. A breast cancer that is to be
treated can be typed as receptor positive or receptor negative. A breast
cancer that is to be treated can have multiple receptors each
independently typed as receptor positive or receptor negative. For
example, a breast cancer that can be treated can be "a triple negative
breast cancer" (i.e., typed as ER-negative, PR-negative, and
HER2-negative). A breast cancer that is to be treated can be typed
as being associated with elevated blood levels of CA 15-3, or CA 27-29,
or both.

[0825] A breast cancer that is to be treated can include a localized tumor
of the breast. A breast cancer that is to be treated can include a tumor
of the breast that is associated with a negative sentinel lymph node
(SLN) biopsy. A breast cancer that is to be treated can include a tumor
of the breast that is associated with a positive sentinel lymph node
(SLN) biopsy. A breast cancer that is to be treated can include a tumor
of the breast that is associated with one or more positive axillary lymph
nodes, where the axillary lymph nodes have been staged by any applicable
method. A breast cancer that is to be treated can include a tumor of the
breast that has been typed as having nodal negative status (e.g.,
node-negative) or nodal positive status (e.g., node-positive). A breast
cancer that is to be treated can include a tumor of the breast that has
metastasized to other locations in the body. A breast cancer that is to
be treated can be classified as having metastasized to a location
selected from the group consisting of bone, lung, liver, or brain. A
breast cancer that is to be treated can be classified according to a
characteristic selected from the group consisting of metastatic,
localized, regional, local-regional, locally advanced, distant,
multicentric, bilateral, ipsilateral, contralateral, newly diagnosed,
recurrent, and inoperable.

[0826] A compound of the invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, polymorph or solvate thereof, may be used to treat
or prevent a cell proliferative disorder of the breast, or to treat or
prevent breast cancer, in a subject having an increased risk of
developing breast cancer relative to the population at large. A subject
with an increased risk of developing breast cancer relative to the
population at large is a female subject with a family history or personal
history of breast cancer. A subject with an increased risk of developing
breast cancer relative to the population at large is a female subject
having a germ-line or spontaneous mutation in BRCA1 or BRCA2, or both. A
subject with an increased risk of developing breast cancer relative to
the population at large is a female subject with a family history of
breast cancer and a germ-line or spontaneous mutation in BRCA1 or BRCA2,
or both. A subject with an increased risk of developing breast cancer
relative to the population at large is a female who is greater than 30
years old, greater than 40 years old, greater than 50 years old, greater
than 60 years old, greater than 70 years old, greater than 80 years old,
or greater than 90 years old. A subject with an increased risk of
developing breast cancer relative to the population at large is a subject
with atypical hyperplasia of the breast, ductal carcinoma in situ (DCIS),
intraductal carcinoma, lobular carcinoma in situ (LCIS), lobular
neoplasia, or a stage 0 growth or lesion of the breast (e.g., stage 0 or
grade 0 breast cancer, or carcinoma in situ).

[0827] A breast cancer that is to be treated can histologically graded
according to the Scarff-Bloom-Richardson system, wherein a breast tumor
has been assigned a mitosis count score of 1, 2, or 3; a nuclear
pleiomorphism score of 1, 2, or 3; a tubule formation score of 1, 2, or
3; and a total Scarff-Bloom-Richardson score of between 3 and 9. A breast
cancer that is to be treated can be assigned a tumor grade according to
the International Consensus Panel on the Treatment of Breast Cancer
selected from the group consisting of grade 1, grade 1-2, grade 2, grade
2-3, or grade 3.

[0828] A cancer that is to be treated can be staged according to the
American Joint Committee on Cancer (AJCC) TNM classification system,
where the tumor (T) has been assigned a stage of TX, T1, T1mic, T1a, T1b,
T1c, T2, T3, T4, T4a, T4b, T4c, or T4d; and where the regional lymph
nodes (N) have been assigned a stage of NX, N0, N1, N2, N2a, N2b, N3,
N3a, N3b, or N3c; and where distant metastasis (M) can be assigned a
stage of MX, M0, or M1. A cancer that is to be treated can be staged
according to an American Joint Committee on Cancer (AJCC) classification
as Stage I, Stage IIA, Stage IIB, Stage IIIA, Stage IIIB, Stage IIIC, or
Stage IV. A cancer that is to be treated can be assigned a grade
according to an AJCC classification as Grade GX (e.g., grade cannot be
assessed), Grade 1, Grade 2, Grade 3 or Grade 4. A cancer that is to be
treated can be staged according to an AJCC pathologic classification (pN)
of pNX, pN0, PN0 (I-), PN0 (I+), PN0 (mol-), PN0 (mol+), PN1, PN1(mi),
PN1a, PN1b, PN1c, pN2, pN2a, pN2b, pN3, pN3a, pN3b, or pN3c.

[0829] A cancer that is to be treated can include a tumor that has been
determined to be less than or equal to about 2 centimeters in diameter. A
cancer that is to be treated can include a tumor that has been determined
to be from about 2 to about 5 centimeters in diameter. A cancer that is
to be treated can include a tumor that has been determined to be greater
than or equal to about 3 centimeters in diameter. A cancer that is to be
treated can include a tumor that has been determined to be greater than 5
centimeters in diameter. A cancer that is to be treated can be classified
by microscopic appearance as well differentiated, moderately
differentiated, poorly differentiated, or undifferentiated. A cancer that
is to be treated can be classified by microscopic appearance with respect
to mitosis count (e.g., amount of cell division) or nuclear pleiomorphism
(e.g., change in cells). A cancer that is to be treated can be classified
by microscopic appearance as being associated with areas of necrosis
(e.g., areas of dying or degenerating cells). A cancer that is to be
treated can be classified as having an abnormal karyotype, having an
abnormal number of chromosomes, or having one or more chromosomes that
are abnormal in appearance. A cancer that is to be treated can be
classified as being aneuploid, triploid, tetraploid, or as having an
altered ploidy. A cancer that is to be treated can be classified as
having a chromosomal translocation, or a deletion or duplication of an
entire chromosome, or a region of deletion, duplication or amplification
of a portion of a chromosome.

[0830] A cancer that is to be treated can be evaluated by DNA cytometry,
flow cytometry, or image cytometry. A cancer that is to be treated can be
typed as having 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90% of cells
in the synthesis stage of cell division (e.g., in S phase of cell
division). A cancer that is to be treated can be typed as having a low
S-phase fraction or a high S-phase fraction.

[0831] As used herein, a "normal cell" is a cell that cannot be classified
as part of a "cell proliferative disorder". A normal cell lacks
unregulated or abnormal growth, or both, that can lead to the development
of an unwanted condition or disease. Preferably, a normal cell possesses
normally functioning cell cycle checkpoint control mechanisms.

[0832] As used herein, "contacting a cell" refers to a condition in which
a compound or other composition of matter is in direct contact with a
cell, or is close enough to induce a desired biological effect in a cell.

[0833] As used herein, "candidate compound" refers to a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
polymorph or solvate thereof, that has been or will be tested in one or
more in vitro or in vivo biological assays, in order to determine if that
compound is likely to elicit a desired biological or medical response in
a cell, tissue, system, animal or human that is being sought by a
researcher or clinician. A candidate compound is a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
polymorph or solvate thereof. The biological or medical response can be
the treatment of cancer. The biological or medical response can be
treatment or prevention of a cell proliferative disorder. In vitro or in
vivo biological assays can include, but are not limited to, enzymatic
activity assays, electrophoretic mobility shift assays, reporter gene
assays, in vitro cell viability assays, and the assays described herein.

[0834] As used herein, "monotherapy" refers to the administration of a
single active or therapeutic compound to a subject in need thereof. In
one aspect, monotherapy will involve administration of a therapeutically
effective amount of an active compound. For example, cancer monotherapy
with one of the compound of the invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof, to a
subject in need of treatment of cancer. Monotherapy may be contrasted
with combination therapy, in which a combination of multiple active
compounds is administered, preferably with each component of the
combination present in a therapeutically effective amount. In one aspect,
monotherapy with a compound of the invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, polymorph or solvate thereof, is
more effective than combination therapy in inducing a desired biological
effect.

[0835] As used herein, "treating" or "treat" describes the management and
care of a patient for the purpose of combating a disease, condition, or
disorder and includes the administration of a compound of the invention,
or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, to alleviate the symptoms or complications of a disease,
condition or disorder, or to eliminate the disease, condition or
disorder.

[0836] A compound of the t invention, or a pharmaceutically acceptable
salt, prodrug, metabolite, polymorph or solvate thereof, can also be used
to prevent a disease, condition or disorder. As used herein, "preventing"
or "prevent" describes reducing or eliminating the onset of the symptoms
or complications of the disease, condition or disorder.

[0837] As used herein, the term "alleviate" is meant to describe a process
by which the severity of a sign or symptom of a disorder is decreased.
Importantly, a sign or symptom can be alleviated without being
eliminated. In one embodiment, the administration of pharmaceutical
compositions of the invention leads to the elimination of a sign or
symptom, however, elimination is not required. Effective dosages are
expected to decrease the severity of a sign or symptom. For instance, a
sign or symptom of a disorder such as cancer, which can occur in multiple
locations, is alleviated if the severity of the cancer is decreased
within at least one of multiple locations.

[0838] As used herein, the term "severity" is meant to describe the
potential of cancer to transform from a precancerous, or benign, state
into a malignant state. Alternatively, or in addition, severity is meant
to describe a cancer stage, for example, according to the TNM system
(accepted by the International Union Against Cancer (UICC) and the
American Joint Committee on Cancer (AJCC)) or by other art-recognized
methods. Cancer stage refers to the extent or severity of the cancer,
based on factors such as the location of the primary tumor, tumor size,
number of tumors, and lymph node involvement (spread of cancer into lymph
nodes). Alternatively, or in addition, severity is meant to describe the
tumor grade by art-recognized methods (see, National Cancer Institute,
www.cancer.gov). Tumor grade is a system used to classify cancer cells in
terms of how abnormal they look under a microscope and how quickly the
tumor is likely to grow and spread. Many factors are considered when
determining tumor grade, including the structure and growth pattern of
the cells. The specific factors used to determine tumor grade vary with
each type of cancer. Severity also describes a histologic grade, also
called differentiation, which refers to how much the tumor cells resemble
normal cells of the same tissue type (see, National Cancer Institute,
www.cancer.gov). Furthermore, severity describes a nuclear grade, which
refers to the size and shape of the nucleus in tumor cells and the
percentage of tumor cells that are dividing (see, National Cancer
Institute, www.cancer.gov).

[0839] In another aspect of the invention, severity describes the degree
to which a tumor has secreted growth factors, degraded the extracellular
matrix, become vascularized, lost adhesion to juxtaposed tissues, or
metastasized. Moreover, severity describes the number of locations to
which a primary tumor has metastasized. Finally, severity includes the
difficulty of treating tumors of varying types and locations. For
example, inoperable tumors, those cancers which have greater access to
multiple body systems (hematological and immunological tumors), and those
which are the most resistant to traditional treatments are considered
most severe. In these situations, prolonging the life expectancy of the
subject and/or reducing pain, decreasing the proportion of cancerous
cells or restricting cells to one system, and improving cancer
stage/tumor grade/histological grade/nuclear grade are considered
alleviating a sign or symptom of the cancer.

[0840] As used herein the term "symptom" is defined as an indication of
disease, illness, injury, or that something is not right in the body.
Symptoms are felt or noticed by the individual experiencing the symptom,
but may not easily be noticed by others. Others are defined as
non-health-care professionals.

[0841] As used herein the term "sign" is also defined as an indication
that something is not right in the body. But signs are defined as things
that can be seen by a doctor, nurse, or other health care professional.

[0842] Cancer is a group of diseases that may cause almost any sign or
symptom. The signs and symptoms will depend on where the cancer is, the
size of the cancer, and how much it affects the nearby organs or
structures. If a cancer spreads (metastasizes), then symptoms may appear
in different parts of the body.

[0843] As a cancer grows, it begins to push on nearby organs, blood
vessels, and nerves. This pressure creates some of the signs and symptoms
of cancer. If the cancer is in a critical area, such as certain parts of
the brain, even the smallest tumor can cause early symptoms.

[0844] But sometimes cancers start in places where it does not cause any
symptoms until the cancer has grown quite large. Pancreas cancers, for
example, do not usually grow large enough to be felt from the outside of
the body. Some pancreatic cancers do not cause symptoms until they begin
to grow around nearby nerves (this causes a backache). Others grow around
the bile duct, which blocks the flow of bile and leads to a yellowing of
the skin known as jaundice. By the time a pancreatic cancer causes these
signs or symptoms, it has usually reached an advanced stage.

[0845] A cancer may also cause symptoms such as fever, fatigue, or weight
loss. This may be because cancer cells use up much of the body's energy
supply or release substances that change the body's metabolism. Or the
cancer may cause the immune system to react in ways that produce these
symptoms.

[0846] Sometimes, cancer cells release substances into the bloodstream
that cause symptoms not usually thought to result from cancers. For
example, some cancers of the pancreas can release substances which cause
blood clots to develop in veins of the legs. Some lung cancers make
hormone-like substances that affect blood calcium levels, affecting
nerves and muscles and causing weakness and dizziness

[0847] Cancer presents several general signs or symptoms that occur when a
variety of subtypes of cancer cells are present. Most people with cancer
will lose weight at some time with their disease. An unexplained
(unintentional) weight loss of 10 pounds or more may be the first sign of
cancer, particularly cancers of the pancreas, stomach, esophagus, or
lung.

[0848] Fever is very common with cancer, but is more often seen in
advanced disease. Almost all patients with cancer will have fever at some
time, especially if the cancer or its treatment affects the immune system
and makes it harder for the body to fight infection. Less often, fever
may be an early sign of cancer, such as with leukemia or lymphoma.

[0849] Fatigue may be an important symptom as cancer progresses. It may
happen early, though, in cancers such as with leukemia, or if the cancer
is causing an ongoing loss of blood, as in some colon or stomach cancers.

[0850] Pain may be an early symptom with some cancers such as bone cancers
or testicular cancer. But most often pain is a symptom of advanced
disease.

[0851] Along with cancers of the skin (see next section), some internal
cancers can cause skin signs that can be seen. These changes include the
skin looking darker (hyperpigmentation), yellow (jaundice), or red
(erythema); itching; or excessive hair growth.

[0852] Alternatively, or in addition, cancer subtypes present specific
signs or symptoms. Changes in bowel habits or bladder function could
indicate cancer. Long-term constipation, diarrhea, or a change in the
size of the stool may be a sign of colon cancer. Pain with urination,
blood in the urine, or a change in bladder function (such as more
frequent or less frequent urination) could be related to bladder or
prostate cancer.

[0853] Changes in skin condition or appearance of a new skin condition
could indicate cancer. Skin cancers may bleed and look like sores that do
not heal. A long-lasting sore in the mouth could be an oral cancer,
especially in patients who smoke, chew tobacco, or frequently drink
alcohol. Sores on the penis or vagina may either be signs of infection or
an early cancer.

[0854] Unusual bleeding or discharge could indicate cancer. Unusual
bleeding can happen in either early or advanced cancer. Blood in the
sputum (phlegm) may be a sign of lung cancer. Blood in the stool (or a
dark or black stool) could be a sign of colon or rectal cancer. Cancer of
the cervix or the endometrium (lining of the uterus) can cause vaginal
bleeding. Blood in the urine may be a sign of bladder or kidney cancer. A
bloody discharge from the nipple may be a sign of breast cancer.

[0855] A thickening or lump in the breast or in other parts of the body
could indicate the presence of a cancer. Many cancers can be felt through
the skin, mostly in the breast, testicle, lymph nodes (glands), and the
soft tissues of the body. A lump or thickening may be an early or late
sign of cancer. Any lump or thickening could be indicative of cancer,
especially if the formation is new or has grown in size.

[0856] Indigestion or trouble swallowing could indicate cancer. While
these symptoms commonly have other causes, indigestion or swallowing
problems may be a sign of cancer of the esophagus, stomach, or pharynx
(throat).

[0857] Recent changes in a wart or mole could be indicative of cancer. Any
wart, mole, or freckle that changes in color, size, or shape, or loses
its definite borders indicates the potential development of cancer. For
example, the skin lesion may be a melanoma.

[0858] A persistent cough or hoarseness could be indicative of cancer. A
cough that does not go away may be a sign of lung cancer. Hoarseness can
be a sign of cancer of the larynx (voice box) or thyroid.

[0859] While the signs and symptoms listed above are the more common ones
seen with cancer, there are many others that are less common and are not
listed here. However, all art-recognized signs and symptoms of cancer are
contemplated and encompassed by the instant invention.

[0860] Treating cancer can result in a reduction in size of a tumor. A
reduction in size of a tumor may also be referred to as "tumor
regression". Preferably, after treatment, tumor size is reduced by 5% or
greater relative to its size prior to treatment; more preferably, tumor
size is reduced by 10% or greater; more preferably, reduced by 20% or
greater; more preferably, reduced by 30% or greater; more preferably,
reduced by 40% or greater; even more preferably, reduced by 50% or
greater; and most preferably, reduced by greater than 75% or greater.
Size of a tumor may be measured by any reproducible means of measurement.
The size of a tumor may be measured as a diameter of the tumor.

[0861] Treating cancer can result in a reduction in tumor volume. In one
aspect, after treatment, tumor volume is reduced by 5% or greater
relative to its size prior to treatment; more preferably, tumor volume is
reduced by 10% or greater; more preferably, reduced by 20% or greater;
more preferably, reduced by 30% or greater; more preferably, reduced by
40% or greater; even more preferably, reduced by 50% or greater; and most
preferably, reduced by greater than 75% or greater. Tumor volume may be
measured by any reproducible means of measurement.

[0862] Treating cancer results in a decrease in number of tumors. In one
aspect, after treatment, tumor number is reduced by 5% or greater
relative to number prior to treatment; more preferably, tumor number is
reduced by 10% or greater; more preferably, reduced by 20% or greater;
more preferably, reduced by 30% or greater; more preferably, reduced by
40% or greater; even more preferably, reduced by 50% or greater; and most
preferably, reduced by greater than 75%. Number of tumors may be measured
by any reproducible means of measurement. The number of tumors may be
measured by counting tumors visible to the naked eye or at a specified
magnification. In one aspect, the specified magnification is 2×,
3×, 4×, 5×, 10×, or 50×.

[0863] Treating cancer can result in a decrease in number of metastatic
lesions in other tissues or organs distant from the primary tumor site.
In one aspect, after treatment, the number of metastatic lesions is
reduced by 5% or greater relative to number prior to treatment; more
preferably, the number of metastatic lesions is reduced by 10% or
greater; more preferably, reduced by 20% or greater; more preferably,
reduced by 30% or greater; more preferably, reduced by 40% or greater;
even more preferably, reduced by 50% or greater; and most preferably,
reduced by greater than 75%. The number of metastatic lesions may be
measured by any reproducible means of measurement. The number of
metastatic lesions may be measured by counting metastatic lesions visible
to the naked eye or at a specified magnification. Preferably, the
specified magnification is 2×, 3×, 4×, 5×,
10×, or 50×.

[0864] Treating cancer can result in an increase in average survival time
of a population of treated subjects in comparison to a population
receiving carrier alone. In one aspect, the average survival time is
increased by more than 30 days; more preferably, by more than 60 days;
more preferably, by more than 90 days; and most preferably, by more than
120 days. An increase in average survival time of a population may be
measured by any reproducible means. An increase in average survival time
of a population may be measured, for example, by calculating for a
population the average length of survival following initiation of
treatment with an active compound. An increase in average survival time
of a population may also be measured, for example, by calculating for a
population the average length of survival following completion of a first
round of treatment with an active compound.

[0865] Treating cancer can result in an increase in average survival time
of a population of treated subjects in comparison to a population of
untreated subjects. In one aspect, the average survival time is increased
by more than 30 days; by more than 60 days; by more than 90 days; and
most preferably, by more than 120 days. An increase in average survival
time of a population may be measured by any reproducible means. An
increase in average survival time of a population may be measured, for
example, by calculating for a population the average length of survival
following initiation of treatment with an active compound. An increase in
average survival time of a population may also be measured, for example,
by calculating for a population the average length of survival following
completion of a first round of treatment with an active compound.

[0866] Treating cancer can result in increase in average survival time of
a population of treated subjects in comparison to a population receiving
monotherapy with a drug that is not a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof. In one aspect, the average survival time is increased
by more than 30 days; more preferably, by more than 60 days; more
preferably, by more than 90 days; and most preferably, by more than 120
days. An increase in average survival time of a population may be
measured by any reproducible means. An increase in average survival time
of a population may be measured, for example, by calculating for a
population the average length of survival following initiation of
treatment with an active compound. An increase in average survival time
of a population may also be measured, for example, by calculating for a
population the average length of survival following completion of a first
round of treatment with an active compound.

[0867] Treating cancer can result in a decrease in the mortality rate of a
population of treated subjects in comparison to a population receiving
carrier alone. Treating cancer can result in a decrease in the mortality
rate of a population of treated subjects in comparison to an untreated
population. Treating cancer can result in a decrease in the mortality
rate of a population of treated subjects in comparison to a population
receiving monotherapy with a drug that is not a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
analog or derivative thereof. In one aspect, the mortality rate is
decreased by more than 2%; more preferably, by more than 5%; more
preferably, by more than 10%; and most preferably, by more than 25%. A
decrease in the mortality rate of a population of treated subjects may be
measured by any reproducible means. A decrease in the mortality rate of a
population may be measured, for example, by calculating for a population
the average number of disease-related deaths per unit time following
initiation of treatment with an active compound. A decrease in the
mortality rate of a population may also be measured, for example, by
calculating for a population the average number of disease-related deaths
per unit time following completion of a first round of treatment with an
active compound.

[0868] Treating cancer can result in a decrease in tumor growth rate. In
one aspect, after treatment, tumor growth rate is reduced by at least 5%
relative to number prior to treatment; more preferably, tumor growth rate
is reduced by at least 10%; more preferably, reduced by at least 20%;
more preferably, reduced by at least 30%; more preferably, reduced by at
least 40%; more preferably, reduced by at least 50%; even more
preferably, reduced by at least 50%; and most preferably, reduced by at
least 75%. Tumor growth rate may be measured by any reproducible means of
measurement. Tumor growth rate can be measured according to a change in
tumor diameter per unit time.

[0869] Treating cancer can result in a decrease in tumor regrowth.
Preferably, after treatment, tumor regrowth is less than 5%; more
preferably, tumor regrowth is less than 10%; more preferably, less than
20%; more preferably, less than 30%; more preferably, less than 40%; more
preferably, less than 50%; even more preferably, less than 50%; and most
preferably, less than 75%. Tumor regrowth may be measured by any
reproducible means of measurement. Tumor regrowth is measured, for
example, by measuring an increase in the diameter of a tumor after a
prior tumor shrinkage that followed treatment. A decrease in tumor
regrowth is indicated by failure of tumors to reoccur after treatment has
stopped.

[0870] Treating or preventing a cell proliferative disorder can result in
a reduction in the rate of cellular proliferation. In one aspect, after
treatment, the rate of cellular proliferation is reduced by at least 5%;
more preferably, by at least 10%; more preferably, by at least 20%; more
preferably, by at least 30%; more preferably, by at least 40%; more
preferably, by at least 50%; even more preferably, by at least 50%; and
most preferably, by at least 75%. The rate of cellular proliferation may
be measured by any reproducible means of measurement. The rate of
cellular proliferation is measured, for example, by measuring the number
of dividing cells in a tissue sample per unit time.

[0871] Treating or preventing a cell proliferative disorder can result in
a reduction in the proportion of proliferating cells. In one aspect,
after treatment, the proportion of proliferating cells is reduced by at
least 5%; more preferably, by at least 10%; more preferably, by at least
20%; more preferably, by at least 30%; more preferably, by at least 40%;
more preferably, by at least 50%; even more preferably, by at least 50%;
and most preferably, by at least 75%. The proportion of proliferating
cells may be measured by any reproducible means of measurement.
Preferably, the proportion of proliferating cells is measured, for
example, by quantifying the number of dividing cells relative to the
number of nondividing cells in a tissue sample. The proportion of
proliferating cells can be equivalent to the mitotic index.

[0872] Treating or preventing a cell proliferative disorder can result in
a decrease in size of an area or zone of cellular proliferation. In one
aspect, after treatment, size of an area or zone of cellular
proliferation is reduced by at least 5% relative to its size prior to
treatment; more preferably, reduced by at least 10%; more preferably,
reduced by at least 20%; more preferably, reduced by at least 30%; more
preferably, reduced by at least 40%; more preferably, reduced by at least
50%; even more preferably, reduced by at least 50%; and most preferably,
reduced by at least 75%. Size of an area or zone of cellular
proliferation may be measured by any reproducible means of measurement.
The size of an area or zone of cellular proliferation may be measured as
a diameter or width of an area or zone of cellular proliferation.

[0873] Treating or preventing a cell proliferative disorder can result in
a decrease in the number or proportion of cells having an abnormal
appearance or morphology. In one aspect, after treatment, the number of
cells having an abnormal morphology is reduced by at least 5% relative to
its size prior to treatment; more preferably, reduced by at least 10%;
more preferably, reduced by at least 20%; more preferably, reduced by at
least 30%; more preferably, reduced by at least 40%; more preferably,
reduced by at least 50%; even more preferably, reduced by at least 50%;
and most preferably, reduced by at least 75%. An abnormal cellular
appearance or morphology may be measured by any reproducible means of
measurement. An abnormal cellular morphology can be measured by
microscopy, e.g., using an inverted tissue culture microscope. An
abnormal cellular morphology can take the form of nuclear pleiomorphism.

[0874] One aspect of the invention includes methods of preventing or
treating a metabolic disorder comprising administering a pharmaceutical
composition that includes an effective amount of one of the compounds of
any of the formulae or compounds described herein. A metabolic disorder
is any disorder that involves an alteration in the normal metabolism of
carbohydrates, lipids, proteins, water, and nucleic acids. Examples of
metabolic disorders include type 1 and type 2 diabetes mellitus,
complications of diabetes (such as e.g. retinopathy, nephropathy or
neuropathies, diabetic foot, ulcers, macroangiopathies), metabolic
acidosis or ketosis, reactive hypoglycaemia, hyperinsulinaemia, glucose
metabolic disorder, insulin resistance, metabolic syndrome,
dyslipidaemias of different origins, atherosclerosis and related
diseases, obesity, high blood pressure, chronic heart failure, edema and
hyperuricaemia. Metabolic syndrome is one type of metabolic disorder.
Metabolic syndrome is a combination of medical disorders that, when they
occurr together, increase the risk of developing cardiovascular disease
and diabetes. Metabolic syndrome is also known as metabolic syndrome X,
cardiometabolic syndrome, syndrome X, insulin resistance syndrome,
Reaven's syndrome (named for Gerald Reaven), and CHAOS (in Australia).

[0875] As used herein, the term "selectively" means tending to occur at a
higher frequency in one population than in another population. The
compared populations can be cell populations. In one aspect, a compound
of the invention, or a pharmaceutically acceptable salt, prodrug,
metabolite, polymorp In one aspect, a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, acts selectively to modulate one molecular target (e.g.,
PKM2) but does not significantly modulate another molecular target (e.g.,
PKM1). The invention also provides a method for selectively inhibiting or
activating the activity of an enzyme, such as a kinase (e.g., PKM2).
Preferably, an event occurs selectively in population A relative to
population B if it occurs greater than two times more frequently in
population A as compared to population B. An event occurs selectively if
it occurs greater than five times more frequently in population A. An
event occurs selectively if it occurs greater than ten times more
frequently in population A; more preferably, greater than fifty times;
even more preferably, greater than 100 times; and most preferably,
greater than 1000 times more frequently in population A as compared to
population B. For example, cell death would be said to occur selectively
in cancer cells if it occurred greater than twice as frequently in cancer
cells as compared to normal cells.

[0876] A compound of the invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, polymorph or solvate thereof, can modulate the
activity of a molecular target (e.g., PKM2). Modulating refers to
stimulating or inhibiting an activity of a molecular target. In one
aspect, a compound of the invention, or a pharmaceutically acceptable
salt, prodrug, metabolite, polymorph or solvate thereof, modulates the
activity of a molecular target if it stimulates or inhibits the activity
of the molecular target by at least 10% relative to the activity of the
molecular target under the same conditions but lacking only the presence
of said compound. In one aspect, a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, modulates the activity of a molecular target if it
stimulates or inhibits the activity of the molecular target by at least
2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least
50-fold, at least 100-fold relative to the activity of the molecular
target under the same conditions but lacking only the presence of said
compound. The activity of a molecular target may be measured by any
reproducible means. The activity of a molecular target may be measured in
vitro or in vivo. For example, the activity of a molecular target may be
measured in vitro or in vivo by an enzymatic activity assay.

[0877] A compound of the invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, polymorph or solvate thereof, does not significantly
modulate the activity of a molecular target if the addition of the
compound does not stimulate or inhibit the activity of the molecular
target by greater than 10% relative to the activity of the molecular
target under the same conditions but lacking only the presence of said
compound.

[0878] As used herein, the term "isozyme selective" means preferential
inhibition or stimulation of a first isoform of an enzyme in comparison
to a second isoform of an enzyme (e.g., preferential inhibition or
stimulation of a kinase isozyme alpha in comparison to a kinase isozyme
beta).

[0879] A change in enzymatic activity caused by a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
polymorph or solvate thereof, can be measured in the disclosed assays.
The change in enzymatic activity can be characterized by the change in
the extent of phosphorylation of certain substrates. As used herein,
"phosphorylation" refers to the addition of phosphate groups to a
substrate, including proteins and organic molecules; and, plays an
important role in regulating the biological activities of proteins.
Preferably, the phosphorylation assayed and measured involves the
addition of phosphate groups to tyrosine residues. The substrate can be a
peptide or protein.

[0880] In some assays, immunological reagents, e.g., antibodies and
antigens, are employed. Fluorescence can be utilized in the measurement
of enzymatic activity in some assays. As used herein, "fluorescence"
refers to a process through which a molecule emits a photon as a result
of absorbing an incoming photon of higher energy by the same molecule.
Specific methods for assessing the biological activity of the disclosed
compounds are described in the examples.

[0881] Activating refers to placing a composition of matter (e.g., protein
or nucleic acid) in a state suitable for carrying out a desired
biological function. A composition of matter capable of being activated
also has an unactivated state. An activated composition of matter may
have an inhibitory or stimulatory biological function, or both.

[0882] Elevation refers to an increase in a desired biological activity of
a composition of matter (e.g., a protein or a nucleic acid). Elevation
may occur through an increase in concentration of a composition of
matter.

[0883] Treating cancer or a cell proliferative disorder can result in cell
death, and preferably, cell death results in a decrease of at least 10%
in number of cells in a population. More preferably, cell death means a
decrease of at least 20%; more preferably, a decrease of at least 30%;
more preferably, a decrease of at least 40%; more preferably, a decrease
of at least 50%; most preferably, a decrease of at least 75%. Number of
cells in a population may be measured by any reproducible means. A number
of cells in a population can be measured by fluorescence activated cell
sorting (FACS), immunofluorescence microscopy and light microscopy.
Methods of measuring cell death are as shown in Li et al., Proc Natl Acad
Sci US A. 100(5): 2674-8, 2003. In an aspect, cell death occurs by
apoptosis.

[0884] In one aspect, an effective amount of a compound of the invention,
or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, is not significantly cytotoxic to normal cells. A
therapeutically effective amount of a compound is not significantly
cytotoxic to normal cells if administration of the compound in a
therapeutically effective amount does not induce cell death in greater
than 10% of normal cells. A therapeutically effective amount of a
compound does not significantly affect the viability of normal cells if
administration of the compound in a therapeutically effective amount does
not induce cell death in greater than 10% of normal cells. In an aspect,
cell death occurs by apoptosis.

[0885] Contacting a cell with a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, can induce or activate cell death selectively in cancer
cells. Administering to a subject in need thereof a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
polymorph or solvate thereof, can induce or activate cell death
selectively in cancer cells. Contacting a cell with a compound of the
invention, or a pharmaceutically acceptable salt, prodrug, metabolite,
polymorph or solvate thereof, can induce cell death selectively in one or
more cells affected by a cell proliferative disorder. In one aspect,
administering to a subject in need thereof a compound of the invention,
or a pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, induces cell death selectively in one or more cells
affected by a cell proliferative disorder.

[0886] One skilled in the art may refer to general reference texts for
detailed descriptions of known techniques discussed herein or equivalent
techniques. These texts include Ausubel et al., Current Protocols in
Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al.,
Molecular Cloning, A Laboratory Manual (3rd edition), Cold Spring
Harbor Press, Cold Spring Harbor, N.Y. (2000); Coligan et al., Current
Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current
Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The
Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical
Sciences, Mack Publishing Co., Easton, Pa., 18th edition (1990).
These texts can, of course, also be referred to in making or using an
aspect of the invention.

[0887] "Combination therapy" (or "co-therapy") includes the administration
of a compound of the invention and at least a second agent as part of a
specific treatment regimen intended to provide the beneficial effect from
the co-action of these therapeutic agents. The beneficial effect of the
combination includes, but is not limited to, pharmacokinetic or
pharmacodynamic co-action resulting from the combination of therapeutic
agents. Administration of these therapeutic agents in combination
typically is carried out over a defined time period (usually minutes,
hours, days or weeks depending upon the combination selected).
"Combination therapy" may, but generally is not, intended to encompass
the administration of two or more of these therapeutic agents as part of
separate monotherapy regimens that incidentally and arbitrarily result in
the combinations of the invention.

[0888] "Combination therapy" is intended to embrace administration of
these therapeutic agents in a sequential manner, that is, wherein each
therapeutic agent is administered at a different time, as well as
administration of these therapeutic agents, or at least two of the
therapeutic agents, in a substantially simultaneous manner. Substantially
simultaneous administration can be accomplished, for example, by
administering to the subject a single capsule having a fixed ratio of
each therapeutic agent or in multiple, single capsules for each of the
therapeutic agents. Sequential or substantially simultaneous
administration of each therapeutic agent can be effected by any
appropriate route including, but not limited to, oral routes, intravenous
routes, intramuscular routes, and direct absorption through mucous
membrane tissues. The therapeutic agents can be administered by the same
route or by different routes. For example, a first therapeutic agent of
the combination selected may be administered by intravenous injection
while the other therapeutic agents of the combination may be administered
orally. Alternatively, for example, all therapeutic agents may be
administered orally or all therapeutic agents may be administered by
intravenous injection. The sequence in which the therapeutic agents are
administered is not narrowly critical.

[0889] "Combination therapy" also embraces the administration of the
therapeutic agent(s) as described above in combination with other
biologically active ingredients and/or non-drug therapies (e.g., surgery,
immunotherapy or radiation treatment). Where the combination therapy
comprises a non-drug treatment, the non-drug treatment may be conducted
at any suitable time so long as a beneficial effect from the co-action of
the combination of the therapeutic agent(s) and non-drug treatment is
achieved. For example, in appropriate cases, the beneficial effect is
still achieved when the non-drug treatment is temporally removed from the
administration of the therapeutic agents, perhaps by days or even weeks.

[0890] A compound of the invention, or a pharmaceutically acceptable salt,
prodrug, metabolite, analog or derivative thereof, may be administered in
combination with a second anti-cancer agent. The second anti-cancer agent
(also referred to as an anti-neoplastic agent or anti-proliferative
agent) can be another agent that modulates cancer metabolism, an
alkylating agent; an antibiotic; an anti-metabolite; a detoxifying agent;
an interferon; a polyclonal or monoclonal antibody; an EGFR inhibitor; a
HER2 inhibitor; a histone deacetylase inhibitor; a hormone; a
mitotic inhibitor; an MTOR inhibitor; a multi-kinase inhibitor; a
serine/threonine kinase inhibitor; a tyrosine kinase inhibitors; a
VEGF/VEGFR inhibitor; a taxane or taxane derivative, an aromatase
inhibitor, an anthracycline, a microtubule targeting drug, a
topoisomerase poison drug, an inhibitor of a molecular target or enzyme
(e.g., a kinase inhibitor), a cytidine analogue drug or any
chemotherapeutic, anti-neoplastic or anti-proliferative agent listed in
www.cancer.org/docroot/cdg/cdg--0.asp.

[0911] In another aspect, the second chemotherapeutic agent can be a
cytokine such as G-CSF (granulocyte colony stimulating factor). In
another aspect, a compound of the invention, or a pharmaceutically
acceptable salt, prodrug, metabolite, analog or derivative thereof, may
be administered in combination with radiation therapy. Radiation therapy
can also be administered in combination with a compound of the invention
and another chemotherapeutic agent described herein as part of a multiple
agent therapy. In yet another aspect, a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, analog or
derivative thereof, may be administered in combination with standard
chemotherapy combinations such as, but not restricted to, CMF
(cyclophosphamide, methotrexate and 5-fluorouracil), CAF
(cyclophosphamide, adriamycin and 5-fluorouracil), AC (adriamycin and
cyclophosphamide), FEC (5-fluorouracil, epirubicin, and
cyclophosphamide), ACT or ATC (adriamycin, cyclophosphamide, and
paclitaxel), rituximab, Xeloda (capecitabine), Cisplatin (CDDP),
Carboplatin, TS-1 (tegafur, gimestat and otastat potassium at a molar
ratio of 1:0.4:1), Camptothecin-11 (CPT-11, Irinotecan or Camptosar®)
or CMFP (cyclophosphamide, methotrexate, 5-fluorouracil and prednisone).

[0912] In one embodiment, a compound of the invention, or a
pharmaceutically acceptable salt, prodrug, metabolite, polymorph or
solvate thereof, may be administered with an inhibitor of an enzyme, such
as a receptor or non-receptor kinase. Receptor and non-receptor kinases
of the invention are, for example, tyrosine kinases or serine/threonine
kinases. Kinase inhibitors of the invention are small molecules,
polynucleic acids, polypeptides, or antibodies.

[0915] Throughout the description, where compositions are described as
having, including, or comprising specific components, it is contemplated
that compositions also consist essentially of, or consist of, the recited
components. Similarly, where processes are described as having,
including, or comprising specific process steps, the processes also
consist essentially of, or consist of, the recited processing steps.
Further, it should be understood that the order of steps or order for
performing certain actions are immaterial so long as the invention
remains operable. Moreover, two or more steps or actions may be conducted
simultaneously.

[0916] The compounds, or pharmaceutically acceptable salts thereof, are
administered orally, nasally, transdermally, pulmonary, inhalationally,
buccally, sublingually, intraperintoneally, subcutaneously,
intramuscularly, intravenously, rectally, intrapleurally, intrathecally
and parenterally. In some embodiments, the compound is administered
orally. One skilled in the art will recognize the advantages of certain
routes of administration.

[0917] The dosage regimen utilizing the compounds is selected in
accordance with a variety of factors including type, species, age,
weight, sex and medical condition of the patient; the severity of the
condition to be treated; the route of administration; the renal and
hepatic function of the patient; and the particular compound or salt
thereof employed. An ordinarily skilled physician or veterinarian can
readily determine and prescribe the effective amount of the drug required
to prevent, counter or arrest the progress of the condition.

[0918] Techniques for formulation and administration of compounds of the
invention can be found in Remington: the Science and Practice of
Pharmacy, 19th edition, Mack Publishing Co., Easton, Pa. (1995). In
one aspect, the compounds described herein, and the pharmaceutically
acceptable salts thereof, are used in pharmaceutical preparations in
combination with a pharmaceutically acceptable carrier or diluent.
Suitable pharmaceutically acceptable carriers include inert solid fillers
or diluents and sterile aqueous or organic solutions. The compounds will
be present in such pharmaceutical compositions in amounts sufficient to
provide the desired dosage amount in the range described herein.

[0919] In some embodiments, the compound is prepared for oral
administration, wherein the disclosed compounds or salts thereof are
combined with a suitable solid or liquid carrier or diluent to form
capsules, tablets, pills, powders, syrups, solutions, suspensions and the
like.

[0920] The tablets, pills, capsules, and the like contain from about 1 to
about 99 weight percent of the active ingredient and a binder such as gum
tragacanth, acacias, corn starch or gelatin; excipients such as dicalcium
phosphate; a disintegrating agent such as corn starch, potato starch or
alginic acid; a lubricant such as magnesium stearate; and/or a sweetening
agent such as sucrose, lactose, saccharin, xylitol, and the like. When a
dosage unit form is a capsule, it often contains, in addition to
materials of the above type, a liquid carrier such as a fatty oil.

[0921] In some embodiments, various other materials are present as
coatings or to modify the physical form of the dosage unit. For instance,
in some embodiments, tablets are coated with shellac, sugar or both. In
some embodiments, a syrup or elixir contains, in addition to the active
ingredient, sucrose as a sweetening agent, methyl and propylparabens as
preservatives, a dye and a flavoring such as cherry or orange flavor, and
the like.

[0922] For some embodiments relating to parental administration, the
compounds, or salts, solvates, tautomers or polymorphs thereof, can be
combined with sterile aqueous or organic media to form injectable
solutions or suspensions. In some embodiments, injectable compositions
are aqueous isotonic solutions or suspensions. The compositions may be
sterilized and/or contain adjuvants, such as preserving, stabilizing,
wetting or emulsifying agents, solution promoters, salts for regulating
the osmotic pressure and/or buffers. In addition, they may also contain
other therapeutically valuable substances. The compositions are prepared
according to conventional mixing, granulating or coating methods,
respectively, and contain about 0.1 to 75%, in another embodiment, the
compositions contain about 1 to 50%, of the active ingredient.

[0923] For example, injectable solutions are produced using solvents such
as sesame or peanut oil or aqueous propylene glycol, as well as aqueous
solutions of water-soluble pharmaceutically-acceptable salts of the
compounds. In some embodiments, dispersions are prepared in glycerol,
liquid polyethylene glycols and mixtures thereof in oils. Under ordinary
conditions of storage and use, these preparations contain a preservative
to prevent the growth of microorganisms. The terms "parenteral
administration" and "administered parenterally" as used herein means
modes of administration other than enteral and topical administration,
usually by injection, and includes, without limitation, intravenous,
intramuscular, intraarterial, intrathecal, intracapsular, intraorbital,
intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous,
subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and
intrasternal injection and infusion.

[0924] For rectal administration, suitable pharmaceutical compositions
are, for example, topical preparations, suppositories or enemas.
Suppositories are advantageously prepared from fatty emulsions or
suspensions. The compositions may be sterilized and/or contain adjuvants,
such as preserving, stabilizing, wetting or emulsifying agents, solution
promoters, salts for regulating the osmotic pressure and/or buffers. In
addition, they may also contain other therapeutically valuable
substances. The compositions are prepared according to conventional
mixing, granulating or coating methods, respectively, and contain about
0.1 to 75%, in another embodiment, compositions contain about 1 to 50%,
of the active ingredient.

[0925] In some embodiments, the compounds are formulated to deliver the
active agent by pulmonary administration, e.g., administration of an
aerosol formulation containing the active agent from, for example, a
manual pump spray, nebulizer or pressurized metered-dose inhaler. In some
embodiments, suitable formulations of this type also include other
agents, such as antistatic agents, to maintain the disclosed compounds as
effective aerosols.

[0926] A drug delivery device for delivering aerosols comprises a suitable
aerosol canister with a metering valve containing a pharmaceutical
aerosol formulation as described and an actuator housing adapted to hold
the canister and allow for drug delivery. The canister in the drug
delivery device has a headspace representing greater than about 15% of
the total volume of the canister. Often, the polymer intended for
pulmonary administration is dissolved, suspended or emulsified in a
mixture of a solvent, surfactant and propellant. The mixture is
maintained under pressure in a canister that has been sealed with a
metering valve.

[0927] For nasal administration, either a solid or a liquid carrier can be
used. The solid carrier includes a coarse powder having particle size in
the range of, for example, from about 20 to about 500 microns and such
formulation is administered by rapid inhalation through the nasal
passages. In some embodiments where the liquid carrier is used, the
formulation is administered as a nasal spray or drops and includes oil or
aqueous solutions of the active ingredients.

[0928] Also contemplated are formulations that are rapidly dispersing
dosage forms, also known as "flash dose" forms. In particular, some
embodiments of the invention are formulated as compositions that release
their active ingredients within a short period of time, e.g., typically
less than about five minutes, in another embodiment, less than about
ninety seconds, in another embodiment, less than about thirty seconds and
in another embodiment, in less than about ten or fifteen seconds. Such
formulations are suitable for administration to a subject via a variety
of routes, for example by insertion into a body cavity or application to
a moist body surface or open wound.

[0929] Typically, a "flash dosage" is a solid dosage form that is
administered orally, which rapidly disperses in the mouth, and hence does
not require great effort in swallowing and allows the compound to be
rapidly ingested or absorbed through the oral mucosal membranes. In some
embodiments, suitable rapidly dispersing dosage forms are also used in
other applications, including the treatment of wounds and other bodily
insults and diseased states in which release of the medicament by
externally supplied moisture is not possible.

[0930] "Flash dose" forms are known in the art; see for example,
effervescent dosage forms and quick release coatings of insoluble
microparticles in U.S. Pat. Nos. 5,578,322 and 5,607,697; freeze dried
foams and liquids in U.S. Pat. Nos. 4,642,903 and 5,631,023; melt
spinning of dosage forms in U.S. Pat. Nos. 4,855,326, 5,380,473 and
5,518,730; solid, free-form fabrication in U.S. Pat. No. 6,471,992;
saccharide-based carrier matrix and a liquid binder in U.S. Pat. Nos.
5,587,172, 5,616,344, 6,277,406, and 5,622,719; and other forms known to
the art.

[0931] The compounds of the invention are also formulated as "pulsed
release" formulations, in which the compound is released from the
pharmaceutical compositions in a series of releases (i.e., pulses). The
compounds are also formulated as "sustained release" formulations in
which the compound is continuously released from the pharmaceutical
composition over a prolonged period.

[0932] Also contemplated are formulations, e.g., liquid formulations,
including cyclic or acyclic encapsulating or solvating agents, e.g.,
cyclodextrins, polyethers, or polysaccharides (e.g., methylcellulose), or
in another embodiment, polyanionic β-cyclodextrin derivatives with a
sodium sulfonate salt group separate from the lipophilic cavity by an
alkyl ether spacer group or polysaccharides. In some embodiments, the
agent is methylcellulose. In another embodiment, the agent is a
polyanionic β-cyclodextrin derivative with a sodium sulfonate salt
separated from the lipophilic cavity by a butyl ether spacer group, e.g.,
CAPTISOL® (CyDex Pharmaceuticals Inc., Lenexa, Kans.). One skilled in
the art can evaluate suitable agent/disclosed compound formulation ratios
by preparing a solution of the agent in water, e.g., a 40% by weight
solution; preparing serial dilutions, e.g. to make solutions of 20%, 10,
5%, 2.5%, 0% (control), and the like; adding an excess (compared to the
amount that can be solubilized by the agent) of the disclosed compound;
mixing under appropriate conditions, e.g., heating, agitation,
sonication, and the like; centrifuging or filtering the resulting
mixtures to obtain clear solutions; and analyzing the solutions for
concentration of the disclosed compound.

[0933] All publications and patent documents cited herein are incorporated
herein by reference as if each such publication or document was
specifically and individually indicated to be incorporated herein by
reference. Citation of publications and patent documents is not intended
as an admission that any is pertinent prior art, nor does it constitute
any admission as to the contents or date of the same. The invention
having now been described by way of written description, those of skill
in the art will recognize that the invention can be practiced in a
variety of embodiments and that the foregoing description and examples
below are for purposes of illustration and not limitation of the claims
that follow.

EXAMPLES

[0934] The following examples are illustrative of certain embodiments of
the inventions and should not be considered to limit the scope of the
invention. The reagents used can be either commercially obtained or can
be prepared by standard procedures described in the literature. It is
intended that the scope of this invention will cover all isomers
(enantiomeric and diastereomeric) and all mixtures, including but not
limited to racemic mixtures. The isomeric forms of the compounds of this
invention may be separated or resolved using methods known to those
skilled in the art or by synthetic methods that are stereospecific or
asymmetric.

General Methods:

[0935] All air or moisture sensitive reactions were performed under
positive pressure of nitrogen with oven-dried glassware. Anhydrous
solvents such as pyridine, tetrahydrofuran (THF), acetonitrile, ethanol
and methanol were obtained from Bio-Lab. Hydrazine hydrate was purchased
from Sigma-Aldrich and used as received. Sulfuric acid, acetic anhydride
and ammonium hydroxide were purchased from Bio-Lab. Analytical HPLC
experiments were carried out using Gemini-NX 3 μM C18 column (110
Å, 150×4.6 mm) on a Waters 2996 instrument equipped with a
photodiode array detector. The mobile phase consisted of acetonitrile and
water (each containing 0.1% trifluoroacetic acid). A gradient of 0% to
100% acetonitrile over 11 minutes was used during the purification.
Fraction collection was triggered by UV detection (254 nM). Analytical
analysis was performed on a Waters 2695 LC/MS (separation module). The
mobile phase consisted of acetonitrile and water (each containing 0.1%
formic acid). A Gemini-NX 3 μM C18 column (110 Å, 150×4.6
mm) was used. Purity determination was performed using a Waters 2996
instrument equipped with a photodiode array detector.

[0936] Preparative purification was performed with CombiFlash Rf,
flash chromatography system. The column used was a Silica Redi sep
Rf, flash column. Column chromatography was performed using silica
gel 60 (particle size 0.04-0.06 mm) Preparative chiral separation was
performed on SFC-80 (Thar, Waters) using Chiralpak AD-H column (Daicel, 5
μm, 20×250 mm) at column temperature: 40° C. The mobile
phase consisted of methanol/CO2=45/55 at flow 40 g/min and back
pressure 100 Bar. 1H NMR (300 MHz) spectra were recorded on Bruker
Avance-300 spectrometer, in DMSO-d6 as an internal standard. All of the
analogues for assay have purity greater than 95%.

Example 1

Synthesis of 2-pyrazoline derivatives

[0937] One aspect of embodiments of the invention is stereoselective
preparation of 2-pyrazolines of the following general structure [4]:

[0939] Referring to Scheme 1, the reaction of chalcones [1] and related
α,β-unsaturated ketones with hydrazines [2] is the most
popular procedure for the synthesis of 2-pyrazolines [5]. This reaction
can be conducted under various conditions. The most commonly used method
is the reaction of compounds [1] and [2] in acetic acid solution to
prepare 2-pyrazoline [5].

[0941] Synthesis of 2-pyrazolines [5] can also be achieved under alkaline
conditions by using pyridine as catalyst in ethanolic solution
(Anjaneyulu, A. S. R. et al. (1995) Indian J. Chem. 34B, 933.) or as
solvent (Sammour, A. E. (1964) Tetrahedron 20, 1067.). In some cases, the
two reactants were refluxed in alcoholic solution without catalyst to
provide 2-pyrazolines [5]. Based on various experimental findings, it has
been concluded that the reaction of α,β-enones [1] with
hydrazines [2] yields 2-pyrazolines [5] via hydrazone intermediates [3]
under acidic conditions. However, if piperidine was used as the catalyst,
the β-hydrazinoketones [4] were formed as intermediates, the ring
closure of which gives 2-pyrazolines [5] (Al-Farkh, Y. A. et al. (1979)
Chem. Pharm. Bull. 27, 257).

[0942] As shown in Scheme 2, compounds according to certain embodiments of
the invention were prepared as follows. In the first step, substituted
p-aminoacetophenone was condensed with chlorosulphonylchloride derivative
to give sulphonamidoacetophenone [6], which was then treated with
arylaldehydes [7] to give 4-(substituted sulphoneamido) chalcones [8].
The obtained product, α,β-unsaturated ketones [8], was treated
with substituted hydrazine hydrate [9] in ethanol and in glacial acetic
acid to yield the expected 2-pyrazoline product [10].

##STR00337##

These compounds of the invention include the individual optical isomers
having an asymmetric carbon at the 5-position of the 2-pyrazoline ring.

[0943] The enantiomers were resolved by known methods such as preparative
HPLC using a 10 cm CHIRALPAK® AD column (US 20090042966), or
deliberately prepared by enantioselective synthesis of 2-pyrazoline
(Angewandte Chemie International Edition (Dec. 21, 2009), 48(52),
9975-9978). Both enantiomers were tested for their PKM2 activity.

[0945] Benjamin List (Angewandte Chemie International Edition (Dec. 21,
2009), 48(52), 9975-9978) reported the catalytic asymmetric preparation
of 2-pyrazolines using 3,3'-bis-(9-anthracenyl) substituted binol
phosphate in high yield and high e.e. According to List's procedure the
reactions were run in Ar atmosphere with enones, phenylhydrazines MS 4A
and 10% mol of phosphoric acid as catalyst in chlorobenzene at 30°
C.

[0948] Ethanesulfonyl chloride was added dropwise to a stirred solution of
1-(4-aminophenyl)ethanone and 1 mL of pyridine. The reaction was stirred
at room temperature overnight. When complete as determined by HPLC, using
the H2O-Acetonitrile (ACN) gradient given below with a
Gemini®-NX C18, μm, 110 Å, 150×4.6 mm chromatography
column, as well as by LCMS, the THF was evaporated. The evaporation
residue was dissolved in 50 mL ethyl acetate, washed with 100 mL of 1M
KHSO4, and then brine and dried on Na2SO4. The solvent was
evaporated and the product used for the next step without further
purification (3.57 g, yield 60.4%)

[0950] N-(4-acetylphenyl)ethanesulfonamide and
2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde were refluxed in MeOH with
40% KOH/H2O for 3 hours, and then stirred at room temperature
overnight. The reaction was evaporated, redissolved in EtOAc and then
washed with 1N KHSO4 and finally with brine. The organic phase was
dried, and crystallized from EtOH. The chalcone product absorbs strongly
at 360 nm and eluted at 8/2 EtOAc/PE (1.2 g, 36.4% yield).

Step 3:

[0951] (E)-N-(4-(3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acryloyl)phenyl)et-
hanesulfonamide was stirred in EtOH (20 mL) with a large excess of
hydrazine at reflux for 3 hours. Reaction mixture was evaporated and used
further step without purification.

Step 4:

[0952] N-(4-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4,5-dihydro-1H-pyrazo-
l-3-yl)phenyl)ethanesulfonamide was stirred for 3 hours in a 1/1 mixture
of acetic anhydride and pyridine at room temperature. The reaction
mixture was evaporated to dryness, and was stirred into an ammonium
hydroxide in MeOH solution at room temperature for 3 hours. After all the
starting material was consumed, the crude reaction mixture was
evaporated, and separated on CombiFlash® (EA:PE) to provide 116 mg of
product (16.4% yield). HPLC: Rt=8.11 minutes, 95.5% purity, as determined
by the protocol above. MS-(ES+) Calcd. for C17H17NO6S2 429.49. found
430.51 (M+H).

[0955] 2,6-difluorobenzene-1-sulfonyl chloride was added dropwise to a
stirred solution of 1-(4-aminophenyl)ethanone and 1 mL of pyridine. The
reaction was stirred at room temperature overnight. When complete as
determined by HPLC using the protocol described above, as well as by
LCMS, THF was evaporated, the evaporation residue was dissolved in 50 mL
ethyl acetate, washed with 100 mL of 1M KHSO4, and then washed with
brine and dried on Na2SO4. The solvent was evaporated and the residue was
used for the next step without further purification (2.4 g, yield 46%).

Step 2:

[0956] N-(4-acetylphenyl)-2,6-difluorobenzenesulfonamide and
4-methoxybenzaldehyde were refluxed in MeOH with 40% KOH/H2O for 3
hours, and then stirred at room temperature overnight. The reaction
mixture was evaporated, redissolved in EtOAc and washed with 1N KHSO4 and
then brine. The organic phase was dried, evaporated and separated on
CombiFlash®. The chalcone product absorbs strongly at 360 nm, eluting
at 8/2 EtOAc/PE (292 mg, 8.7% yield).

Step 3:

[0957] (E)-2,6-difluoro-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)benzenesu-
lfonamide was stirred in EtOH (20 mL) with a large excess of hydrazine at
reflux for 3 hours. The reaction mixture was evaporated and used in the
next step without further purification.

Step 4:

[0958] 2,6-difluoro-N-(4-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)-
phenyl)benzenesulfonamide was stirred for 3 hours in a 1:1 mixture of
acetic anhydride and pyridine, at room temperature. The reaction mixture
was evaporated to dryness, and the product,
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-N--
((2,6-difluorophenyl)sulfonyl)acetamide, was stirred in ammonium hydroxide
in a MeOH solution at room temperature for 3 hours. After all the
starting material was consumed, the crude reaction mixture was
evaporated, and separated on CombiFlash® (EA:PE) to 6 mg of the final
product (7% yield). Product Analysis: HPLC: Rt=9.085 minutes, 93.49%
purity, as determined by the protocol in Example 2 above. MS-(ES+) Calcd.
for C17H17NO6S2 485.5. found 486.52 (M+H).

[0961] 4-fluorobenzene-1-sulfonyl chloride was added dropwise to a stirred
solution of 1-(4-aminophenyl)ethanone and 1 mL of pyridine under N2.
The reaction was stirred at room temperature overnight. When complete as
determined by HPLC using the protocol described in Example 2, as well as
by TLC (8/2 PE/EtOAc), the THF was evaporated, the evaporation residue
was dissolved in 50 mL ethyl acetate, washed with 100 mL cold 0.5M HCl
and then with brine and finally dried on Na2SO4. The solvent
was evaporated and the product was used in the next step without further
purification (1250 mg, yield 58%).

Step II:

[0962] N-(4-acetylphenyl)-4-fluorobenzenesulfonamide and
4-methoxybenzaldehyde were refluxed in MeOH with sulfuric acid (1 mL) for
3 hours, and then stirred at room temperature overnight. The reaction was
evaporated, redissolved in EtOAc and then washed twice with 50 mL 0.5M
NaOH and finally with brine. The organic phase was dried, evaporated and
separated on CombiFlash®. The chalcone product absorbs strongly at
360 nm and eluted at 8/2 EtOAc/PE. Step II was repeated twice, until
enough product accumulated (1000 mg, ˜80% pure, overall yield 20%).

Step III:

[0963] (E)-4-fluoro-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)benzenesulfon-
amide was stirred in EtOH (20 mL) with a large excess of hydrazine (70%
aqueous solution) at room temperature for 3 hours. The reaction was
evaporated and separated on CombiFlash®. Product-containing fractions
were combined and used without further purification.

Step IV:

[0964] 4-fluoro-N-(4-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phen-
yl)benzenesulfonamide was stirred for 3 hours in 1:1 mixture of acetic
anhydride and pyridine at room temperature. The reaction mixture was
evaporated to dryness, and crudely separated on CombiFlash®. No
complete purification was achieved as determined by MS and HPLC.

[0966] 72 mg of racemic
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-4--
fluorobenzenesulfonamide (Compound 6A) was resolved into its two
individual enantiomers by preparative HPLC using a CHIRALPAK® AD-H
(Daicel) 250×20 mm, 5 μm column run at 40° C.
Chromatography was performed using a mobile phase of 45/55Methanol/CO2 at
a flow rate of 40 g/min. and 10 g of the compound was loaded per
injection. FIG. 2 shows HPLC chromatograms of the starting racemate (FIG.
2A) and each of the individual enantiomers (FIGS. 2B and 2C). A
1H-NMR analysis for each of the individual enantiomers is shown in
FIG. 3A (R-enantiomer) and FIG. 3B (S-enantiomer), respectively.

[0969] 2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonyl chloride was added
dropwise to a stirred solution of 1-(4-aminophenyl)ethanone and 1 mL of
pyridine under N2. The reaction was stirred at room temperature
overnight. When complete as determined by HPLC using the protocol
described in Example 2 above, as well as by TLC (8/2 PE/EtOAc), the THF
was evaporated, the evaporation residue was dissolved in 50 mL ethyl
acetate, washed with 100 mL cold 0.5M HCl and then with brine and finally
dried on Na2SO4. The solvent was evaporated and the product was
used in the next step without further purification (605 mg, yield 80%).

Step II:

[0970] 4-methoxybenzaldehyde and
N-(4-acetylphenyl)-2,3-dihydrobenzo[b][1,4]dioxine-6-sulfonamide were
refluxed in MeOH with sulfuric acid (1 mL) for 3 hours, and then stirred
at room temperature overnight. The reaction was evaporated, redissolved
in EtOAc and then washed twice with 50 mL 0.5M NaOH and finally with
brine. The organic phase was dried, evaporated and separated on
CombiFlash®. The chalcone product absorbs strongly at 360 nm and
eluted at 8/2 EtOAc/PE (˜600 mg, ˜70% pure, overall yield
20%).

Step III:

[0971] (E)-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)-2,3-dihydrobenzo[b][1-
,4]dioxine-6-sulfonamide was stirred in EtOH (20 mL) with a large excess
of hydrazine (70% aqueous solution) at room temperature for 3 hours. The
reaction was evaporated and separated on CombiFlash®.
Product-containing fractions were combined and used further without
complete purification.

Step IV:

[0972] N-(4-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)-2,3-d-
ihydrobenzo[b][1,4]dioxine-6-sulfonamide was stirred for 3 hours in a 1:1
mixture of acetic anhydride and pyridine at room temperature. The
reaction mixture was evaporated to dryness, and crudely separated on
CombiFlash®. No complete purification was achieved as determined by
MS and HPLC.

[0977] Methanesulfonyl chloride was added dropwise to a stirred solution
of 1-(indolin-5-yl)ethanone and 5 mL of pyridine under N2. The
reaction was stirred at room temperature overnight. When complete as
determined by HPLC using the protocol described in Example 2 above, as
well as by TLC (8/2 PE/EtOAc), the solvent was evaporated, the
evaporation residue was dissolved in 50 mL ethyl acetate, washed with 100
mL cold 0.5M HCl and then with brine and finally dried on
Na2SO4. The solvent was evaporated and the product was used in
the next step without further purification (400 mg, yield 38%).

Step II:

[0978] 1-(1-(methylsulfonyl)indolin-5-yl)ethanone and
2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde were refluxed in MeOH with
sulfuric acid (1 mL) for 3 hours, and then stirred at room temperature
overnight. The reaction was evaporated, redissolved in EtOAc and then
washed twice with 50 mL 0.5M NaOH and then brine. The organic phase was
dried, evaporated and separated on CombiFlash® (yield 60%).

Step III:

[0979] (E)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1-(1-(methylsulfonyl)in-
dolin-5-yl)prop-2-en-1-one was stirred in EtOH (20 mL) with a large excess
of hydrazine (70% aqueous solution) at room temperature for 3 hours. The
reaction was evaporated and separated on CombiFlash®.
Product-containing fractions were combined and used without further
purification.

[0983] 4-acetylbenzene-1-sulfonyl chloride was added dropwise to a stirred
solution of excess ethanamine and 1 mL of pyridine under N2. The reaction
was stirred at room temperature overnight. When complete as determined by
HPLC using the protocol described in Example 2 above, as well as by TLC
(8/2 PE/EtOAc), the pyridine was evaporated, the evaporation residue was
dissolved in 50 mL ethyl acetate, and then washed with 100 mL cold 0.5M
HCl and then with brine and finally dried on Na2SO4. The solvent was
evaporated and the product was used for the next step without further
purification (500 mg, yield 91%, HPLC Rt=7.529 min).

Step II:

[0984] 3-acetyl-N-ethylbenzenesulfonamide and 4-methoxybenzaldehyde were
refluxed in MeOH with sulfuric acid (1 mL) for 3 hours, and then stirred
at room temperature overnight. The reaction was evaporated, redissolved
in EtOAc and then washed twice with 50 mL 0.5M NaOH and then with brine.
The organic phase was dried, evaporated and separated on CombiFlash®.
The chalcone product absorbs strongly at 360 nm and eluted at 8/2
EtOAc/PE (˜300 mg isolated, 98% pure, Rt=9.025 minutes).

Step III:

[0985] (E)-N-ethyl-4-(3-(4-methoxyphenyl)acryloyl)benzenesulfonamide was
stirred in EtOH (20 mL) with a large excess of hydrazine (70% aqueous
solution) at room temperature for 3 hours. The reaction was evaporated
and separated on CombiFlash®. Product-containing fractions were
combined and used without further purification.

[0989] 4-Fluorobenzene-1-sulfonyl chloride (20.0 g, 103.0 mmol, 1.1 equiv)
was added dropwise to a stirred solution of 4'-Aminoacetophenone (12.6 g,
93.6 mmol, 1.0 equiv) in pyridine (500 mL). The reaction was stirred
overnight at rt. Monitoring by HPLC and LCMS indicated that the reaction
was completed. The solvent was evaporated under reduced pressure. A
solution of HCl 1N (200 mL) and EtOAc (200 mL) were added. The organic
layer was separated and the aqueous phase was extracted twice with EtOAc
(2×200 mL). The combined organic phase was dried over
Na2SO4 and the solvent was evaporated under reduced pressure to
yield the pure product: 26.2 gr, 95.5% yield.

[0991] (E)-4-fluoro-N-(4-(3-(4-methoxyphenyl)acryloyl)phenyl)benzene
sulfonamide (26.2 g, 63.6 mmol, 1.0 equiv) and pyridine (5 ml) were
stirred in EtOH (200 mL) with large excess of hydrazine (10 mL) at reflux
for 3 hours. The solvent was evaporated and the mixture was transferred
to the next step without further treatment: 22.9 gr, 85% yield.

[0992] 4-fluoro-N-(4-(5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phen-
yl)benzenesulfonamide (22.9 g, 53.8 mmol, 1.0 equiv) was dissolved in
pyridine (50 mL). Acetic anhydride (20 mL) was added and the reaction
mixture was stirred for 2 h at rt. Monitoring by HPLC and LCMS indicated
that the reaction was completed. The solvent was evaporated and the
diacetylation product was transferred to the next step without further
treatment: 24.0 gr, 87.5% yield.

[1091] The ability of several test compounds to activate PKM2 was
determined and the results are presented in Table 1 below. PKM2 performs
the following enzymatic reaction, where the PKM2 substrates, PEP
(phosphoenolpyruvate) and ADP, are converted to pyruvate and ATP as
follows:

[1094] PKM2 activity assays were performed in duplicates at each
concentration. The luminescence data were analyzed using the computer
software, GraphPad PRISM®. In the absence of the compound, the
luminescence was defined as 0% activity. The percent activity in the
presence of each compound was calculated according to the following
equation:

% Activity=[(L-Lb)/(Lt-Lb)-1]×100%

where L=the luminescence in the presence of the test compound,
Lb=the luminescence in the absence of PKM2, and Lt=the
luminescence intensity in the absence of the test compound. The %
activity values versus a series of compound concentrations were plotted
using non-linear regression analysis of Sigmoidal dose-response curve
generated with the equation Y=B+(T-B)/1+10.sup.((LogEC50-X)×Hill
Slope), where Y=percent activity, B=minimum percent activity, T=maximum
percent activity, X=logarithm of compound and Hill Slope=slope factor or
Hill coefficient. The AC50 values, shown in Table 2 were determined
for the indicated test compounds as the concentration causing a
half-maximal percent activity.

[1095] Growth inhibitory activity against the human tumor cell lines was
determined using Promega's CellTiter-Glo® assay. The cell lines of
interest were placed in a 96-well microculture plate (Costar® white,
flat bottom #3917) in a total volume of 90 μL/well. After 24 hours of
incubation in a humidified incubator at 37° C. with 5% CO2
and 95% air, 10 μL of serially diluted test compounds in growth medium
were added to each well. After 96 total hours of culture in a CO2
incubator, the plated cells and CellTiter-Glo® (Promega # G7571)
reagents were brought to room temperature to equilibrate for 30 minutes.
100 μL of CellTiter-Glo® reagent was added to each well. The plate
was shaken for 2 minutes and then left to equilibrate for 10 minutes
before reading luminescence on the Tecan GENios microplate reader.

[1096] Percent inhibition of cell growth was calculated relative to
untreated control wells. All tests were performed in duplicate for each
concentration level. The IC50 value for the test compounds was
estimated using Prism 3.03 by curve-fitting the data.

Assay Protocol II

[1097] In a second assay to determine the inhibition of cell proliferation
by a test compound, cell proliferation of the cell line of interest was
measured by a cell proliferation index assay using Fluofarma
(www.fluofarma.com) based technology. This assay is based on the dilution
rate of a fluorescent membrane marker, which is a direct function of the
number of cell divisions. Briefly, the assay is performed by loading the
cells with a non-toxic fluorescent phospholipid analog before the
seeding. The probe inserts stably into the cell membrane, after which the
probe does not exchange with neighboring cells or the surrounding medium;
however, the probe will be distributed between daughter cells after
division. Flow cytometry analysis of the fluorescent probe is performed
after the loading of the cells both prior to, as well as after treatment
with various concentrations of the test compound. The dilution rate of
the fluorescent probe at the single cell level is directly correlated to
the number of cell divisions.

Results

[1098] The results for the indicated tumor cells lines of inhibition of
cellular proliferation by the indicated test compounds, following the
numbering of Table 1, are provided below (all results are as measured
using Assay Protocol I, except as otherwise noted):

[1100] Furthermore, as shown in FIG. 5, when Compound 1A was used in
combination with 5-FU, a standard of care first line chemotherapy for
colorectal cancer, on HT-29-cell, a colorectal cancer cell line, an
effect that was at least additive was observed.

[1102] Furthermore, as shown in FIG. 6, cell cycle analysis of Compound
13A--i.e., the S-enantiomer of Compound 6A, both following the numbering
of Table 1, was performed on H1299 cells. After 48 hours, most cells were
arrested at the G1/S phase, in other words, the compound induces growth
arrest and stops the cell cycle at the G1 phase, just before DNA
synthesis, consistent with a mechanism of action where the cell is
deprived of the building blocks necessary for biosynthesis.

[1122] Day 0 Cells were seeded at 3000 cells/well in 100 μl full media
in 96-well culture plates (60 wells/plate, external wells filled with 100
μl PBS) and incubated overnight. [1123] Day 1 On the following day,
full media was changed to the tested media and compounds were added in
0.5% DMSO final. [1124] Day 2-5 Cells were incubated over 72 hr. [1125]
Day 5 Cell proliferation was assessed using XTT proliferation assay as
follows:

Assay Principles

[1126] The assay is based on the ability of metabolic active cells to
reduce the tetrazolium salt XTT to orange colored compounds of formazan.
The dye formed is water soluble and the dye intensity can be read at a
given wavelength with a spectrophotometer. The intensity of the dye is
proportional to the number of metabolic active cells. The use of
multiwell plates and an ELISA reader enables testing a large number of
samples and obtaining easy and rapid results. The test procedure includes
cultivation of cells in a 96-well plate, adding the XTT reagent and
incubation for 2-24 hours. During incubation an orange color is formed,
the intensity of which can be measured with a spectrophotometer, in this
instance with an ELISA reader. The greater the number of active cells in
the well, the greater the activity of mitochondria enzymes, and the
higher the concentration of the dye formed, which can then be measured
and quantitated.

Procedure

[1127] 1. As described in the above protocol, the cells were
cultivated in a flat 96-well plate. To each well was added 100 μl of
growth media. The cells were incubated in a CO2 incubator at
37° C. In most cases cells were used to assay proliferation after
24-96 hours. Each test included a blank containing complete medium
without cells (see 7: background control). [1128] 2. The XTT reagent
solution and the activation solution were defrosted immediately prior to
use in a 37° C. bath. The solution was swirled gently until clear
solutions were obtained. [1129] 3. For each plate (96 wells), a reaction
solution was prepared by adding 0.1 ml activation solution to 5 ml XTT
reagent. [1130] 4. 50 μl of the reaction solution was added to each
well and the plate was incubated in an incubator for 2-24 hours (usually,
2-5 hours are sufficient). [1131] 5. The plate was shaken gently to
evenly distribute the dye in the wells. [1132] 6. The absorbance of the
samples was measured against a background control as a blank (see 7) with
a spectrophotometer (ELISA reader) at a wavelength of 450-500 nanometer.
In order to measure reference absorbance (to measure non-specific
readings), a wavelength of 630-690 nanometer was used and subtracted from
the 450-500 nanometer measurement. [1133] 7. Background control (blank):
Slight spontaneous absorbance around 450-500 nanometer occurs in the
culture medium incubated with the XTT reagent. This background absorbance
depends on the culture medium, pH, incubation time and length of exposure
to light. One or more blank control wells without cells were prepared by
adding the same volume of culture medium and XTT Reagent solution as used
in the experiment. The average absorbance of the blank control wells was
subtracted from that of the other wells.

[1134] Data was analyzed using GraphPad Prism software. The proliferation
changes of H460 cells and HT-29 cells under effects of media conditions
or test compounds are presented in FIGS. 8 and 9.

Example 10-2A

In Vitro Cell Proliferation Assays of Racemates and Enantiomers

[1135] The aim of the current study was to evaluate the effect of some
compounds of the invention on H460 cell proliferation under serine-free
and lipoprotein-free media conditions.

The following racemate-enantiomerA-enantiomerB "trios" were tested:

Racemate Compound 1A

Enantiomer A Compound 2A

Enantiomer B Compound 3A

Racemate Compound 6A

Enantiomer A Compound 12A

Enantiomer B Compound 13A

Racemate Compound 18A

Enantiomer A Compound 29A

Enantiomer B Compound 30A

Racemate Compound 19A

Enantiomer A Compound 39A

Enantiomer B Compound 40A

Racemate Compound 25A

Enantiomer A Compound 35A

Enantiomer B N/A

Racemate Compound 26A

Enantiomer A Compound 37A

Enantiomer B Compound 38A

[1136] Control compound Compound 13A

[1137] Each compound was tested in 2 concentrations (10 and 1 μM) in
duplicates.

[1140] At Day 0, cells were seeded at 3000 cells/well in 100 μl full
media in 96-well culture plates (60

wells/plate, external wells filled with 120 μl PBS) and incubated
overnight. The rest of protocols, including XTT proliferation assay and
data analysis, were the same as those in Example 10-2. Results are shown
in FIGS. 10C and 10D.

1. Cells were grown according to the ATCC conditions. 2. Cell feeding
(passaging) was timed such that the cells were in exponential growth
phase at the time of the assay.

Proliferation Assay Using the Celltiter-Glo Luminescent Assay

[1142] 3. On day 1, H1299 cells were counted. Cell numbers were adjusted
to the desired cell concentration in Media 1: RPMI 1640 Invitrogen
11879020 (that contained no glucose or pyruvate) with 10% FBS, and 1 mM
D-Glucose (4 μl of 2.5 M D-glucose G8769 was added in preparing 10 ml
RPMI media with 1 mM glucose). A 200 μl of H1299 cell suspension was
added to appropriate wells in the 96-well plates, and incubated at
37° C. in the CO2 cell incubator under normal growing
conditions for overnight. 4. On day 2, a 100 mM stock concentration of
test compounds in 100% DMSO was prepared and serially diluted with 100%
DMSO to 33.33 mM, 11.11 mM, and 3.7 mM. A 1:1000 dilution was made to
each concentration in media 1 (yielding 0.1% final DMSO concentration).
The media was aspirated completely from the cell plate. Each 100 μl of
the following solutions (100 μM, 33.33 μM, 11.11 μM, and 3.7
μM) was added to the cells. DMSO in a final concentration of 0.1%, and
media without DMSO, were added to the cells and used as a negative
control. Empty wells around the experimental wells were filled with PBS.
The plate was sealed with parafilm to reduce evaporation. 5. The plate
was incubated under normal conditions (5% CO2, and 95% air), for 96
hours at 37° C. 6. On day 6 (after 96 hr incubation), the plate
was equilibrated to room temperature for approximately 30 minutes. A 100
μl of CellTiter-Glo Reagent was added in each well of the plate.
Contents were mixed for 2 minutes on an orbital shaker to induce cell
lysis. The plate was incubated at room temperature for 10 minutes to
stabilize luminescent signal. Luminescence was recorded with Flexstation
3.

Efficacy and Safety of
N-(4-(1-acetyl-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-3-yl)phenyl)eth-
anesulfonamide in a HT-29 Xenograft Mouse Model

[1144] This example illustrates the efficacy and safety of a compound
according to embodiments of the present invention, i.e., Compound 1A,
using a HT-29 xenograft mouse model (a colorectal cancer model).

Animals and Animal Housing:

[1145] Animals

[1146] Species: Mus Musculus

[1147] Strain: BALB/c nude

[1148] Age: 6-8 weeks

[1149] Sex: female

[1150] Body weight: 18-22 g

[1151] Housing Conditions

[1152] The mice were kept in Individual Ventilation Cages at constant
temperature and humidity with 3 animals in each cage.

[1153] Temperature: 20-26° C.

[1154] Humidity 40-70%.

[1155] Cages: Made of polycarbonate. The size is 300 mm×180
mm×150 mm. The bedding material is corn cob, which was changed
twice per week.

[1158] Cage identification: the identification labels for each cage
contain the following information: number of animals, sex, strain, date
received, treatment, study number, group number, and the starting date of
the treatment.

[1159] Animal identification: Animals were marked by ear coding.

Experimental Methods and Procedures:

[1160] Cell Culture

[1161] The HT-29 cells were maintained in vitro as a monolayer culture in
McCoy's 5A medium supplemented with 10% heat inactivated fetal bovine
serum, 100 U/ml penicillin and 100 μg/ml streptomycin at 37° C.
in an atmosphere of 5% CO2 in air. The tumor cells were routinely
subcultured twice weekly by trypsin-EDTA treatment. The cells growing in
an exponential growth phase were harvested and counted for tumor
inoculation.

Tumor Inoculation

[1162] 65 mice were inoculated subcutaneously at the right flank with
3.0×106 HT-29 tumor cells in 0.1 ml of serum-free medium for
tumor development. The treatments were started when the tumor size
reached approximately 75 (50-100) mm3. The test article
administration and the animal numbers in each group are shown in the
following experiment design Table 5.

Ensured that formulation was homogenous immediately before use by gently
turning the tube up and down (The test article formulation was prepared
before each dosing).

[1163] Observations

[1164] All the procedures related to animal handling, care, and the
treatment in this study were performed according to approved guidelines a
following the guidance of the Association for Assessment and
Accreditation of Laboratory Animal Care (AAALAC). At the time of routine
monitoring, the animals were checked for any effects of tumor growth and
treatments on normal behavior such as mobility, food and water
consumption (by looking only), body weight gain/loss (body weights were
measured thrice weekly), eye/hair matting and any other abnormal effect.
Death and observed clinical signs were recorded on the basis of the
numbers of animals within each subset.

[1165] Tumor Measurements and Endpoints

[1166] The major endpoint was to see if the tumor growth can be delayed or
mice can be cured. Tumor size was measured three times weekly in two
dimensions using a caliper, and the volume was expressed in mm3
using the formula: V=0.5 a×b2 where a and b are the long and
short diameters of the tumor, respectively. The tumor size was then used
for calculations of both T-C and TGI values. T-C was calculated with T as
the median time (in days) required for the treatment group tumors to
reach a predetermined size (e.g., 1,000 mm3), and C as the median
time (in days) for the control group tumors to reach the same size. The
TGI (in percent)=(T-C)/C*100% represents the tumor growth inhibition
rate, T and C were the mean volume of the treated and control groups,
respectively, on a given day. Tumor weight was measured at the study
termination. The T/C value (in percent) was calculated where T and C are
the mean tumor weights of the treated and control groups, respectively.

[1172] In this study, the therapeutic efficacy of Compound 1A as a single
agent in the treatment of HT-29 xenograft models was evaluated. No
significant body weight loss was observed in all the treatment groups.
The results of tumor sizes in different groups at different time points
after tumor inoculation are shown in FIG. 4A, for a dosing schedule of
400 mg/kg QD. The (Tumor Growth Inhibition) TGI for this dosing schedule
was 42%. The dosing schedules of 200 mg/kg QD and 100 mg/kg Q2D also
yielded statistically significantly anti-tumor activity. In particular,
>50% TGI was reached by day ten for two dosing schedules, i.e., 400
mg/kg QD and 200 mg/kg QD (See FIG. 4B).

[1173] In addition, even at the highest dosages levels of 400 mg/kg QD,
Compound 1A a good in vivo safety profile was observed. No significant
body weight loss was observed in all the treatment groups (See FIG. 4c),
and pharmacokinetic analysis of the blood samples also demonstrate good
safety profiles (See FIG. 4D). This data suggests that as a PKM2
activator, Compound 1A, effects mainly cancer cells, while leaving the
metabolism of normal cells relatively unaltered.

[1175] H1299 (NCI-H1299) NSCLC cells were obtained from the American Type
Culture Collection, which reports the cell line to have originated from a
lymph node metastasis and to lack p53 expression. The cell line was
maintained as exponentially growing cultures in RPMI-1640 medium
supplemented with 10% fetal bovine serum, 2 mM glutamine, 100 units/mL
penicillin G sodium, 100 μg/mL streptomycin sulfate, 25 μg/mL
gentamicin, 10 mM HEPES, and 0.075% sodium bicarbonate. The tumor cells
were cultured in tissue culture flasks in a humidified incubator at
37° C., in an atmosphere of 5% CO2 and 95% air.

Tumor Implantation and Measurement

[1176] H1299 tumor cells were harvested during log phase growth and
suspended in cold PBS. Each nude mouse was inoculated subcutaneously in
the right flank with 0.2 mL of the cell suspension (1×107
cells). The tumors were periodically calipered in two dimensions to
monitor size as the mean volume approached the desired 90-130 mm3
range. Tumor size was calculated by the following formula:

Tumor Volume ( mm 3 ) = w 2 × l 2
##EQU00001##

where w=width and l=length, in mm, of the tumor. Tumor weight may be
estimated with the assumption that 1 mg is equivalent to 1 mm3 of
tumor volume. Thirteen days after tumor implantation, on D1 of the study,
mice with individual tumor volumes ranging from 75 to 162 mm3 were
sorted into four treatment groups with group mean tumor volumes of 104
mm3.

Test Articles

[1177] Compound 13A (MW 467.51, code-named XT26) was provided as a powder
stored at -20° C., and protected from light during storage and
handling. Dosing suspensions, in 0.5% carboxymethyl cellulose and 1%
Tween® 80 in deionized water (Vehicle), were prepared fresh for each
dose, and kept at 4° C. post formulation. Gemcitabine
(Gemzar®, Lilly, 38 mg/mL, Lot # A866884A) was stored at room
temperature. A fresh 12 mg/mL gemcitabine dosing solution was prepared on
each treatment day by diluting an aliquot of the stock solution with
saline.

Treatment Plan

[1178] Mice were treated in accordance with the protocol in Table 7,
except for the footnoted schedule modifications in Group 4.

TABLE-US-00020
TABLE 7
Protocol Design for the H1299-e281 Study
Treatment Regimen 1
Group n Agent mg/kg Route Schedule
1 12 Vehicle -- ip bid × 28 first day 1
dose
2 6 Gemcitabine 120 ip q3d × 4
3 12 XT26 100 ip bid × 28 first day 1
dose
4 12 XT26 200 ip bid × 28 first day 1
dose
Annotation: Vehicle = 0.5% carboxymethyl cellulose and 1% Tween ® 80
in deionized water
Protocol changes:
Group 1 tumor volume endpoint was reached on Day 21; at the client's
request, the study was converted from a TGI assay to a TGD assay and
dosing continued. Group 4 dosing stopped after b.i.d. × 8 treatment
because of mortality and continued weight loss. Following improved health
and weight gain, dosing at 200 mg/kg resumed on Day 17 on a qd schedule;
however, the Day 19 dose was omitted by error. Sampling protocols for
Groups 1 and 4 were added while the study was in progress.

[1179] Dosing began on D1 in four groups of mice (n=12/group in Groups 1,
3, and 4; n=6 in Group 2). XT26 and its vehicle were administered
intraperitoneally (i.p.) twice daily for 28 days (b.i.d.×28),
starting with the p.m. dose on D1 and ending with the a.m. dose on D29.
Gemcitabine was administered i.p. once daily at three-day intervals for
four doses (q3d×4). In all groups, the dosing volume of 10 ml/kg
(0.2 ml/20 g mouse) was scaled to the weight of each individual animal,
as measured twice weekly.

Group 1 mice received the XT26 vehicle b.i.d.×28, and served as the
controls for the study. Group 2 received gemcitabine at 120 mg/kg. Group
3 was to receive XT26 at 100 mg/kg b.i.d.×28; on D21, four mice
(Animals 1, 3, 4, and 5) erroneously received 200 mg/kg XT26 for their
a.m. dose. Group 4 was to receive XT26 at 200 mg/kg b.i.d.×28, but
dosing stopped on D9 (b.i.d.×8) because of toxicity. Group 4 dosing
at 200 mg/kg resumed on D17 on a qd (once daily)×13 dosing
schedule. Because of a scheduling error, the D19 dose for Group 4 mice
was omitted; qd dosing occurred on Days 17, 18, and 20-28.

Endpoint and Tumor Growth Delay (TGD) Analysis

[1180] Tumors were calipered twice weekly for the duration of the study,
and each animal was euthanized when its neoplasm reached the
predetermined endpoint volume (1200 mm3) or at the end of the study,
whichever came first. Animals that exited the study for tumor growth were
documented as euthanized for tumor progression (TP), with the date of
euthanasia. The time to endpoint (TTE) for each mouse was calculated by
the following equation:

T T E = log 10 ( endpoint volume ) -
b m ##EQU00002##

where TTE is expressed in days, endpoint volume is expressed in mm3,
b is the intercept, and m is the slope of the line obtained by linear
regression of a log-transformed tumor growth data set. The data set
consists of the first observation that exceeded the endpoint volume used
in analysis and the three consecutive observations that immediately
preceded the attainment of this endpoint volume. The calculated TTE is
usually less than the TP date, the day on which an animal was euthanized
for tumor size. Animals that did not reach the endpoint volume were
assigned a TTE value equal to the last day for which measurements were
available (D28). Any animal classified as dead from treatment-related
(TR) causes was assigned a TTE value equal to the day of death. Any
animal that was euthanized for sampling (ES) was excluded from the
analysis. Any animal dead from non-treatment-related (NTR) causes was to
be excluded from TTE calculations. Treatment efficacy was determined from
tumor growth delay (TGD), which is defined as the increase in the median
TTE, in days, for a treatment group compared to the control group:

TGD=T-C

The percent increase in the median TTE, relative to the control group, is

% TGD = T - C C × 100 ##EQU00003##

where:

[1181] T=median TTE for a treatment group, and

[1182] C=median TTE for the designated control group.

MTV and Criteria for Regression Responses

[1183] Treatment efficacy in each group was also determined from the
median tumor volume, MTV(n), which was defined as the median tumor volume
on the last day of the study (D28) in the number of animals remaining (n)
whose tumors had not attained the endpoint volume.

[1184] Treatment efficacy may also be determined from the incidence and
magnitude of regression responses observed during the study. Treatment
may cause partial regression (PR) or complete regression (CR) of the
tumor in an animal. In a PR response, the tumor volume is 50% or less of
its D1 volume for three consecutive measurements during the course of the
study, and equal to or greater than 13.5 mm3 for one or more of
these three measurements. In a CR response, the tumor volume is less than
13.5 mm3 for three consecutive measurements during the course of the
study.

Toxicity

[1185] Animals were weighed daily on D1-5, then twice weekly until the
completion of the study. The mice were observed frequently for overt
signs of any adverse, treatment-related side effects.

Sampling

[1186] On D10, three mice in Group 1 (Animals 4, 8, and 12) were sampled
for blood (0.3 mL) from the mandibular vein without anesthesia. A portion
of each blood sample (80 μL) was diluted 1:3 (with K-EDTA as
anticoagulant) for CBC analysis, as described below. The remainder of
each sample was processed for serum and stored at 4° C. until it
was transmitted at ambient temperature to ANTECH for clinical chemistry
analysis. On D10, three mice in Group 4 (Animals 2, 6, and 10) were
euthanized by terminal cardiac puncture under CO2 anesthesia and the
full blood volume was collected. A portion of this blood sample (80
μL) was utilized for CBC analysis with differential; another portion
(20 μL) was diluted with three volumes of deionized water, frozen at
-80° C., and shipped on dry ice to Dynamix; and the remainder was
processed for serum which was transmitted to ANTECH for clinical
chemistry analysis.

[1187] On D16, blood was collected from the mandibular veins of three
Group 4 mice (Animals 1, 8, and 12) for CBC analyses. D22 blood samples
were not collected because the specified Group 1 mice (Animals 2, 7, and
9) had previously exited the study for tumor progression.

On D10, both kidneys and the liver were harvested from each euthanized
Group 4 animal. Each organ was weighed separately, fixed overnight in 10%
neutral buffered formalin, and transferred to 70% ethanol. The list of
organ weights is provided in Table 11.

[1188] CBCs with differentials were determined using a Cell-Dyn® 3700
System (Abbott Diagnostics) for automated hematology analyses. Red blood
cells and platelets were measured by electrical impedance. White blood
cells were counted and differentiated into granulated (neutrophils,
basophils, and eosinophils) or agranulated (lymphocytes and monocytes)
cell types by flow cytometry, and hemoglobin concentrations were
determined spectrophotometrically.

Statistical and Graphical Analyses

[1189] All statistical and graphical analyses and were performed with
Prism 3.03 (GraphPad) for Windows. Animals that exited the study for
sampling purposes were excluded from these analyses. Survival was
analyzed by the Kaplan-Meier method, based on TTE values. The logrank
test compared the survival experiences (survival curves) of two groups.
The two-tailed statistical analyses were conducted at P=0.05. Prism
reports results as non-significant (ns) at P>0.05, significant
(symbolized by "*") at 0.01<P≦0.05, very significant ("*") at
0.001<P≦0.01 and extremely significant ("***") at
P≦0.001.

[1190] A scatter plot was constructed to show TTE values for individual
animals, by group. Group median tumor volumes were graphed on a semi-log
plot as functions of time. When an animal exited the study because of
tumor size or TR death, the final tumor volume recorded for the animal
was included with the data used to calculate the median volume at
subsequent time points. The tumor growth curve was truncated when TR
mortality exceeded 10%. The percentage of animals in each group remaining
in the study versus time was presented in a Kaplan-Meier survival plot.
Group mean BW changes were graphed as percent change, ±SEM, from D1.
Tumor growth and BW change curves were truncated when the tumors in more
than 50% of the assessable animals in a group had progressed to the
volume endpoint.

[1191] Table 12 summarizes group treatment responses and reports the
logrank test significance of survival extensions. No tumors regressed
during this study. FIG. 10 is a scatter plot of individual TTE values, by
group. FIGS. 11A and 11B show median tumor growth and the Kaplan-Meier
survival curves.

[1192] Group 1 mice (n=12) received the XT26 vehicle (0.5% carboxymethyl
cellulose and 1% Tween® 80 in deionized water) i.p. b.i.d.×28
and served as controls for all analyses. The median TTE for Group 1 mice,
18.7 days, established a maximum possible TGD of 9.3 days (50%) in this
28-day study (Table 12). Eleven Group 1 tumors attained the 1200 mm3
volume endpoint, and one animal remained on D28 with an 847 mm3
tumor. Group 1 TTEs ranged from 12.3 to 28.0 days (FIG. 10).

Response to Gemcitabine Therapy (Group 2)

[1193] In Group 2 (n=6), treatment with 120 mg/kg gemcitabine i.p.
q3d×4 resulted in an assigned median TTE of 28.0 days,
corresponding to the maximum possible TGD of 9.3 days (50%), and
significant survival extension (P<0.01; logrank test, Table 12). Five
(5/6) Group 2 mice remained on study on D28 with an MTV of 600 mm3.
The Group 2 median tumor volume decreased between D7 and D14, but
subsequent median tumor growth resembled that observed in the control
group (FIG. 11A).

Response to XT26Therapies (Groups 3 and 4)

[1194] In Group 3 (n=12), mice were to receive 100 mg/kg XT26 i.p.
b.i.d.×28. On D21, four mice (Animals 1, 3, 4, and 5) erroneously
received 200 mg/kg for the a.m. dose. It was concluded that the dosing
error had no substantial impact on the overall response. The Group 3
treatment resulted in a median TTE of 23.2 days, corresponding to a
4.5-day TGD (24%), and significant survival extension (P<0.05, Table
12). Three (3/12) Group 3 mice survived to D28 with an MTV of 1080
mm3. One TR death occurred in Group 3 on D17, prior to the D21
dosing error.

[1195] In Group 4 (n=12), treatment with 200 mg/kg XT26 i.p. b.i.d.
resulted in four TR deaths on Days 9-11; the b.i.d. treatment was
discontinued after the a.m. dose on D9. The median tumor growth curve for
Group 4 (solid line) was curtailed on D7 because mortality exceeded 10%
by the subsequent measurement day (FIG. 11A). The curtailed median tumor
growth curve for Group 4 is similar to the curve for Group 3. After three
Group 4 mice were euthanized for sampling on D10, five mice remained on
study in this group. As there were no further deaths, and these animals
regained weight by D17, dosing resumed, but on a qd treatment schedule.
The animals were actually dosed qd on Days 17, 18, and 20-28; omission of
the D19 dose was due to a scheduling error. After exclusion of the three
sampled animals, the median TTE for nine Group 1 mice was 21.2 days,
corresponding to a 2.5-day TGD (13%). For informational purposes, median
tumor growth in the five mice that remained after D10 was represented in
FIG. 11A by a dotted line, which was similar to the curve for Group 3.
According to the survival curve for these five mice, the discontinuous
200 mg/kg XT26 therapy afforded little or no survival advantages relative
to the vehicle treatment (FIG. 11B). One Group 4 mouse survived to D28
with a 527 mm3 tumor.

[1197] While the invention has been described in conjunction with the
detailed description thereof, the foregoing description is intended to
illustrate and not limit the scope of the invention, which is defined by
the scope of the appended claims. Other aspects, advantages, and
modifications are within the scope of the following claims. It will be
understood by those skilled in the art that various changes in form and
details may be made therein without departing from the scope of the
invention encompassed by the appended claims.

Patent applications by Avihai Yacovan, Gedera IL

Patent applications by Nili Schutz, Tel-Aviv IL

Patent applications in class The additional hetero ring consists of two nitrogens and three carbons

Patent applications in all subclasses The additional hetero ring consists of two nitrogens and three carbons